abstracts.csv

Journal,Title,Authors,Author_Information,Abstract,DOI,Misc
"
1. Cancer Manag Res. 2019 Aug 6;11:7455-7472. doi: 10.2147/CMAR.S201177. eCollection
2019.","The relevance between the immune response-related gene module and clinical traits
in head and neck squamous cell carcinoma.","Song Y(#)(1), Pan Y(#)(1), Liu J(1).","Author information: 
(1)State Key Laboratory of Oral Diseases, National Clinical Research Center for
Oral Diseases, Department of Orthodontics, West China Hospital of Stomatology,
Sichuan University, Chengdu, 610041, People's Republic of China.
(#)Contributed equally","Purpose: Head and neck squamous cell carcinoma (HNSCC) is the sixth most
prevalent cancer in the world, accounting for more than 90% of head and neck
malignant tumors. However, its molecular mechanism is largely unknown. To help
elucidate the potential mechanism of HNSCC tumorigenesis, we investigated the
gene interaction patterns associated with tumorigenesis.
Methods: Weighted gene co-expression network analysis (WGCNA) can help us to
predict the intrinsic relationship or correlation between gene expression.
Additionally, we further explored the combination of clinical information and
module construction.
Results: Sixteen modules were constructed, among which the key module most
closely associated with clinical information was identified. By analyzing the
genes in this module, we found that the latter may be related to the immune
response, inflammatory response and formation of the tumor microenvironment.
Sixteen hub genes were identified-ARHGAP9, SASH3, CORO1A, ITGAL, PPP1R16B,
TBC1D10C, IL10RA, ITK, AKNA, PRKCB, TRAF3IP3, GIMAP4, CCR7, P2RY8, GIMAP7, and
SP140. We further validated these genes at the transcriptional and translation
levels.
Conclusion: The innovative use of a weighted network to analyze HNSCC samples
provides new insights into the molecular mechanism and prognosis of HNSCC.
Additionally, the hub genes we identified can be used as biomarkers and
therapeutic targets of HNSCC, laying the foundation for the accurate diagnosis
and treatment of HNSCC in clinical and research in the future.","DOI: 10.2147/CMAR.S201177 
PMCID: PMC6689548
PMID: 31496804 ","Conflict of interest statement: The authors report no conflicts of interest in
this work."
2. Immunol Rev. 2019 May;289(1):158-172. doi: 10.1111/imr.12743.,G-protein coupled receptors and ligands that organize humoral immune responses.,"Lu E(1), Cyster JG(1).","Author information: 
(1)Howard Hughes Medical Institute and Department of Microbiology and Immunology,
University of California San Francisco, San Francisco, California.","B-cell responses are dynamic processes that depend on multiple types of
interactions. Rare antigen-specific B cells must encounter antigen and
specialized systems are needed-unique to each lymphoid tissue type-to ensure this
happens efficiently. Lymphoid tissue barrier cells act to ensure that pathogens, 
while being permitted entry for B-cell recognition, are blocked from replication 
or dissemination. T follicular helper (Tfh) cells often need to be primed by
dendritic cells before supporting B-cell responses. For most responses,
antigen-specific helper T cells and B cells need to interact, first to initiate
clonal expansion and the plasmablast response, and later to support the germinal 
center (GC) response. Newly formed plasma cells need to travel to supportive
niches. GC B cells must become confined to the follicle center, organize into
dark and light zones, and interact with Tfh cells. Memory B cells need to be
positioned for rapid responses following reinfection. Each of these events
requires the actions of multiple G-protein coupled receptors (GPCRs) and their
ligands, including chemokines and lipid mediators. This review will focus on the 
guidance cue code underlying B-cell immunity, with an emphasis on findings from
our laboratory and on newer advances in related areas. We will discuss our recent
identification of geranylgeranyl-glutathione as a ligand for P2RY8. Our goal is
to provide the reader with a focused knowledge about the GPCRs guiding B-cell
responses and how they might be therapeutic targets, while also providing
examples of how multiple types of GPCRs can cooperate or act iteratively to
control cell behavior.",© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.,"DOI: 10.1111/imr.12743 
PMCID: PMC6464390 [Available on 2020-05-01]
PMID: 30977196  [Indexed for MEDLINE]"
"3. Genes Chromosomes Cancer. 2019 Sep;58(9):619-626. doi: 10.1002/gcc.22748. Epub
2019 Apr 3.","GATA3 germline variant is associated with CRLF2 expression and predicts outcome
in pediatric B-cell precursor acute lymphoblastic leukemia.","Madzio J(1)(2), Pastorczak A(1), Sedek L(3), Braun M(1)(2)(4), Taha J(1),
Wypyszczak K(1), Trelinska J(1), Lejman M(5), Muszynska-Roslan K(6), Tomasik
B(1)(2)(7), Derwich K(8), Koltan A(9), Kazanowska B(10), Irga-Jaworska N(11),
Badowska W(12), Matysiak M(13), Kowalczyk J(5), Styczynski J(9), Fendler
W(7)(14), Szczepanski T(15), Mlynarski W(1).","Author information: 
(1)Department of Pediatrics, Oncology and Hematology, Medical University of Lodz,
Lodz, Poland.
(2)Postgraduate School of Molecular Medicine, Medical University of Warsaw,
Warsaw, Poland.
(3)Department of Microbiology and Immunology, Medical University of Silesia,
Katowice, Poland.
(4)Department of Pathology, Medical University of Lodz, Lodz, Poland.
(5)Department of Pediatric Hematology and Oncology, Medical University of Lublin,
Lublin, Poland.
(6)Department of Pediatric Oncology and Hematology, Medical University of
Bialystok, Bialystok, Poland.
(7)Department of Biostatistics & Translational Medicine, Medical University of
Lodz, Lodz, Poland.
(8)Department of Pediatric Hematology, Oncology and Transplantology, University
of Medical Sciences, Poznan, Poland.
(9)Department of Pediatric Hematology and Oncology, Collegium Medicum, Nicolaus
Copernicus University, Torun, Poland.
(10)Department of Pediatric Hematology, Oncology and Transplantology, Medical
University of Wroclaw, Wroclaw, Poland.
(11)Department of Pediatric Hematology, Gdansk Medical University, Gdansk,
Poland.
(12)Department of Pediatric Hematology and Oncology, University of Warmia and
Mazury, Olsztyn, Poland.
(13)Department of Pediatric Hematology and Oncology, Medical University of
Warsaw, Warsaw, Poland.
(14)Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston,
Massachusetts.
(15)Department of Pediatric Hematology and Oncology, Zabrze Medical University of
Silesia, Katowice, Poland.","The germline variant at rs3824662 in GATA3 is a risk locus for Philadelphia-like 
acute lymphoblastic leukemia (Ph-like ALL), the biological subtype of B-cell
precursor (BCP)-ALL defined by a distinct gene expression profile and the
presence of specific somatic aberrations including rearrangements of CRLF2. In
this study, we investigated whether rs3824662 in GATA3 associates with CRLF2
expression in leukemic cells and predicts prognosis in pediatric BCP-ALL patients
treated according to the ALL Intercontinental Berlin-Frankfurt-Münster (IC BFM)
2009 (n = 645) and the ALL IC BFM 2002 (n = 216) protocols. High expression of
CRLF2 was observed at both protein and mRNA levels (fourfold higher in AA than in
CA + CC) among GATA3 AA variant carriers, independent of the presence of
P2RY8-CRLF2 fusion. Additionally, the AA variant at rs3824662 was a significant
factor affecting minimal residual disease level at the end of induction phase and
overall survival regardless of the risk group and the protocol. The germline
variant at rs3824662 in GATA3 is a prognostic factor which associates with CRLF2 
expression in leukemic cells supporting the hypothesis that GATA3 may have a
regulatory effect on the CRLF2 pathway in pediatric BCP-ALL.","© 2019 Wiley Periodicals, Inc.","DOI: 10.1002/gcc.22748 
PMID: 30859636  [Indexed for MEDLINE]"
"4. Nature. 2019 Mar;567(7747):244-248. doi: 10.1038/s41586-019-1003-z. Epub 2019 Mar
6.","S-Geranylgeranyl-L-glutathione is a ligand for human B cell-confinement receptor 
P2RY8.","Lu E(1), Wolfreys FD(1), Muppidi JR(1)(2), Xu Y(1), Cyster JG(3).","Author information: 
(1)Howard Hughes Medical Institute and Department of Microbiology and Immunology,
University of California, San Francisco, CA, USA.
(2)Lymphoid Malignancies Branch, National Cancer Institute, National Institutes
of Health, Bethesda, MD, USA.
(3)Howard Hughes Medical Institute and Department of Microbiology and Immunology,
University of California, San Francisco, CA, USA. jason.cyster@ucsf.edu.","Germinal centres are important sites for antibody diversification and affinity
maturation, and are also a common origin of B cell malignancies. Despite being
made up of motile cells, germinal centres are tightly confined within B cell
follicles. The cues that promote this confinement are incompletely understood.
P2RY8 is a Gα13-coupled receptor that mediates the inhibition of migration and
regulates the growth of B cells in lymphoid tissues1,2. P2RY8 is frequently
mutated in germinal-centre B cell-like diffuse large B cell lymphoma (GCB-DLBCL) 
and Burkitt lymphoma1,3-6, and the ligand for this receptor has not yet been
identified. Here we perform a search for P2RY8 ligands and find P2RY8 bioactivity
in bile and in culture supernatants of several mouse and human cell lines. Using 
a seven-step biochemical fractionation procedure and a drop-out mass spectrometry
approach, we show that a previously undescribed biomolecule,
S-geranylgeranyl-L-glutathione (GGG), is a potent P2RY8 ligand that is detectable
in lymphoid tissues at the nanomolar level. GGG inhibited the chemokine-mediated 
migration of human germinal-centre B cells and T follicular helper cells, and
antagonized the induction of phosphorylated AKT in germinal-centre B cells. We
also found that the enzyme gamma-glutamyltransferase-5 (GGT5), which was highly
expressed by follicular dendritic cells, metabolized GGG to a form that did not
activate the receptor. Overexpression of GGT5 disrupted the ability of P2RY8 to
promote B cell confinement to germinal centres, which indicates that GGT5
establishes a GGG gradient in lymphoid tissues. This work defines GGG as an
intercellular signalling molecule that is involved in organizing and controlling 
germinal-centre responses. As the P2RY8 locus is modified in several other types 
of cancer in addition to GCB-DLBCL and Burkitt lymphoma, we speculate that GGG
might have organizing and growth-regulatory roles in multiple human tissues.","DOI: 10.1038/s41586-019-1003-z 
PMCID: PMC6640153
PMID: 30842656  [Indexed for MEDLINE]"
"5. Leukemia. 2019 Apr;33(4):893-904. doi: 10.1038/s41375-018-0297-4. Epub 2018 Nov
28.","Single-cell analysis identifies CRLF2 rearrangements as both early and late
events in Down syndrome and non-Down syndrome acute lymphoblastic leukaemia.","Potter N(1), Jones L(2), Blair H(2), Strehl S(3), Harrison CJ(2), Greaves M(1),
Kearney L(1), Russell LJ(4).","Author information: 
(1)The Institute of Cancer Research, London, UK.
(2)Northern Institute for Cancer Research, Newcastle University,
Newcastle-upon-Tyne, UK.
(3)CCRI, Children's Cancer Research Institute, St. Anna Kinderkrebsforschung,
Vienna, Austria.
(4)Northern Institute for Cancer Research, Newcastle University,
Newcastle-upon-Tyne, UK. lisa.russell@newcastle.ac.uk.","Deregulated expression of the type I cytokine receptor, CRLF2, is observed in
5-15% of precursor B-cell acute lymphoblastic leukaemia (B-ALL). We have
previously reported the genomic landscape of patients with CRLF2 rearrangements
(CRLF2-r) using both whole genome and exome sequencing, which identified a number
of potential clonal and sub-clonal genomic alterations. In this study, we aimed
to assess when the CRLF2-r; IGH-CRLF2 or P2RY8-CRLF2, arose during the evolution 
of both Down syndrome-ALL (DS-ALL) and non-DS-ALL. Using fluorescence in situ
hybridisation, we were able to track up to four structural variants in single
cells from 47 CRLF2-r B-ALL patients, which in association with our multiplex
single-cell analysis of a further four patients, permitted simultaneous tracking 
of copy number alterations, structural and single nucleotide variants within
individual cells. We observed CRLF2-r arising as both early and late events in DS
and non-DS-ALL patients. Parallel evolution of discrete clones was observed in
the development of CRLF2-r B-ALL, either involving the CRLF2-r or one of the
other tracked abnormalities. In-depth single-cell analysis identified both linear
and branching evolution with early clones harbouring a multitude of
abnormalities, including the CRLF2-r in DS-ALL patients.","DOI: 10.1038/s41375-018-0297-4 
PMCID: PMC6398588
PMID: 30487598  [Indexed for MEDLINE]"
6. Gigascience. 2018 Jul 1;7(7). doi: 10.1093/gigascience/giy079.,Clinker: visualizing fusion genes detected in RNA-seq data.,"Schmidt BM(1), Davidson NM(1)(2), Hawkins ADK(1), Bartolo R(1), Majewski
IJ(3)(4), Ekert PG(1), Oshlack A(1)(2).","Author information: 
(1)Murdoch Children's Research Institute, The Royal Children's Hospital,
Flemington, Road, Parkville Vic 3052 Australia.
(2)School of Biosciences, University of Melbourne, Parkivlle Vic 3010, Australia.
(3)Division of Cancer and Haematology, The Walter and Eliza Hall Institute of
Medical Research, Parkville Vic 3052, Australia.
(4)Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne,
Parkville Vic 3010, Australia.","Background: Genomic profiling efforts have revealed a rich diversity of oncogenic
fusion genes. While there are many methods for identifying fusion genes from
RNA-sequencing (RNA-seq) data, visualizing these transcripts and their supporting
reads remains challenging.
Findings: Clinker is a bioinformatics tool written in Python, R, and Bpipe that
leverages the superTranscript method to visualize fusion genes. We demonstrate
the use of Clinker to obtain interpretable visualizations of the RNA-seq data
that lead to fusion calls. In addition, we use Clinker to explore multiple fusion
transcripts with novel breakpoints within the P2RY8-CRLF2 fusion gene in B-cell
acute lymphoblastic leukemia.
Conclusions: Clinker is freely available software that allows visualization of
fusion genes and the RNA-seq data used in their discovery.","DOI: 10.1093/gigascience/giy079 
PMCID: PMC6065480
PMID: 29982439  [Indexed for MEDLINE]"
"7. Int J Hematol. 2018 Sep;108(3):312-318. doi: 10.1007/s12185-018-2474-7. Epub 2018
May 21.","Copy number abnormality of acute lymphoblastic leukemia cell lines based on their
genetic subtypes.","Tomoyasu C(1)(2), Imamura T(3), Tomii T(1), Yano M(4), Asai D(5), Goto H(6),
Shimada A(7), Sanada M(8), Iwamoto S(9), Takita J(10), Minegishi M(11), Inukai
T(12), Sugita K(12), Hosoi H(1).","Author information: 
(1)Department of Pediatrics, Graduate School of Medical Science, Kyoto
Prefectural University of Medicine, 465 Kajii-cho, Hirokoji, Kamigyo-ku, Kyoto,
602-8566, Japan.
(2)Department of Pediatrics, National Hospital Organization Maizuru Medical
Center, Maizuru, Japan.
(3)Department of Pediatrics, Graduate School of Medical Science, Kyoto
Prefectural University of Medicine, 465 Kajii-cho, Hirokoji, Kamigyo-ku, Kyoto,
602-8566, Japan. imamura@koto.kpu-m.ac.jp.
(4)Department of Pediatrics, Kyoto City Hospital, Kyoto, Japan.
(5)Department of Pediatrics, Japanese Red Cross Kyoto Daini Hospital, Kyoto,
Japan.
(6)Division of Hemato-Oncology and Regenerative Medicine, Kanagawa Children's
Medical Center, Yokohama, Japan.
(7)Department of Pediatric Hematology/Oncology, Okayama University Hospital,
Okayama, Japan.
(8)Clinical Research Center, National Hospital Organization Nagoya Medical
Center, Nagoya, Japan.
(9)Department of Pediatrics, Mie University Graduate School of Medicine, Tsu,
Japan.
(10)Department of Pediatrics, Graduate School of Medicine, The University of
Tokyo, Tokyo, Japan.
(11)Japanese Red Cross Fukushima Blood Center, Okuma, Japan.
(12)Department of Pediatrics, Yamanashi University, Kofu, Japan.","In this study, we performed genetic analysis of 83 B cell precursor acute
lymphoblastic leukemia (B-ALL) cell lines. First, we performed multiplex
ligation-dependent probe amplification analysis to identify copy number
abnormalities (CNAs) in eight genes associated with B-ALL according to genetic
subtype. In Ph+ B-ALL cell lines, the frequencies of IKZF1, CDKN2A/2B, BTG1, and 
PAX5 deletion were significantly higher than those in Ph- B-ALL cell lines. The
frequency of CDKN2A/2B deletion in KMT2A rearranged cell lines was significantly 
lower than that in non-KMT2A rearranged cell lines. These findings suggest that
CNAs are correlated with genetic subtype in B-ALL cell lines. In addition, we
determined that three B-other ALL cell lines had IKZF1 deletions (YCUB-5, KOPN49,
and KOPN75); we therefore performed comprehensive genetic analysis of these cell 
lines. YCUB-5, KOPN49, and KOPN75 had P2RY8-CRLF2, IgH-CRLF2, and PAX5-ETV6
fusions, respectively. Moreover, targeted capture sequencing revealed that YCUB-5
had JAK2 R683I and KRAS G12D, and KOPN49 had JAK2 R683G and KRAS G13D mutations. 
These data may contribute to progress in the field of leukemia research.","DOI: 10.1007/s12185-018-2474-7 
PMID: 29786757  [Indexed for MEDLINE]"
8. Blood Adv. 2018 Mar 13;2(5):529-533. doi: 10.1182/bloodadvances.2017014704.,"Prognostic impact of kinase-activating fusions and IKZF1 deletions in pediatric
high-risk B-lineage acute lymphoblastic leukemia.","Tran TH(1)(2), Harris MH(3), Nguyen JV(2), Blonquist TM(4), Stevenson KE(4),
Stonerock E(5), Asselin BL(6), Athale UH(7), Clavell LA(8), Cole PD(9), Kelly
KM(10), Laverdiere C(1), Leclerc JM(1), Michon B(11), Schorin MA(12), Welch
JJG(13), Reshmi SC(5), Neuberg DS(4), Sallan SE(14), Loh ML(2), Silverman LB(14).","Author information: 
(1)Division of Pediatric Hematology-Oncology, Charles-Bruneau Cancer Center,
Centre Hospitalier Universitaire Sainte-Justine Research Center, Montréal, QC,
Canada.
(2)Helen Diller Family Cancer Research Center, Department of Pediatrics, Benioff 
Children's Hospital, University of California, San Francisco, San Francisco, CA.
(3)Department of Pathology, Boston Children's Hospital, Boston, MA.
(4)Department of Biostatistics and Computational Biology, Dana-Farber Cancer
Institute, Boston, MA.
(5)Department of Pathology and Laboratory Medicine, Nationwide Children's
Hospital, Columbus, OH.
(6)Department of Pediatrics, University of Rochester School of Medicine and
Wilmot Cancer Institute, Rochester, NY.
(7)Division of Hematology/Oncology, McMaster Children's Hospital, Hamilton Health
Sciences, Hamilton, ON, Canada.
(8)San Jorge Children's Hospital, San Juan, Puerto Rico.
(9)Department of Pediatrics, Montefiore Medical Center, Albert Einstein College
of Medicine, Bronx, NY.
(10)Division of Pediatric Hematology/Oncology/Stem Cell Transplantation, Columbia
University Medical Center, New York, NY.
(11)Département de Pédiatrie, Centre Mère-Enfant Soleil, Centre Hospitalier
Universitaire de l'Université Laval, Québec City, QC, Canada.
(12)Inova Fairfax Hospital for Children, Falls Church, VA.
(13)Division of Pediatric Hematology/Oncology, Hasbro Children's Hospital/Brown
University, Providence, RI; and.
(14)Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston
Children's Hospital, Boston, MA.","Recurrent chromosomal rearrangements carry prognostic significance in pediatric
B-lineage acute lymphoblastic leukemia (B-ALL). Recent genome-wide analyses
identified a high-risk B-ALL subtype characterized by a diverse spectrum of
genetic alterations activating kinases and cytokine receptor genes. This subtype 
is associated with a poor prognosis when treated with conventional chemotherapy
but has demonstrated sensitivity to the relevant tyrosine kinase inhibitors. We
sought to determine the frequency of kinase-activating fusions among National
Cancer Institute (NCI) high-risk, Ph-negative, B-ALL patients enrolled on
Dana-Farber Cancer Institute ALL Consortium Protocol 05-001 and to describe their
associated clinical characteristics and outcomes. Among the 105 patients
screened, 16 (15%) harbored an ABL-class fusion (ETV6-ABL1: n = 1; FOXP1-ABL1: n 
= 1; SFPQ-ABL1: n = 1; ZC3HAV1-ABL2: n = 1) or a fusion activating the JAK-STAT
pathway (P2RY8-CRLF2: n = 8; PAX5-JAK2: n = 4). Sixty-nine percent of patients
with an identified fusion had a concomitant IKZF1 deletion (n = 11). In
univariate analysis, fusion-positivity and IKZF1 deletion were each associated
with inferior event-free survival; IKZF1 deletion retained statistical
significance in multivariable analysis (hazard ratio, 2.64; P = .019). Our
findings support therapy intensification for IKZF1-altered patients, irrespective
of the presence of a kinase-activating fusion.",© 2018 by The American Society of Hematology.,"DOI: 10.1182/bloodadvances.2017014704 
PMCID: PMC5851421
PMID: 29507076  [Indexed for MEDLINE]"
9. Leuk Res. 2018 Mar;66:79-84. doi: 10.1016/j.leukres.2018.01.012. Epub 2018 Feb 3.,"High frequency of intermediate and poor risk copy number abnormalities in
pediatric cohort of B-ALL correlate with high MRD post induction.","Singh M(1), Bhatia P(2), Trehan A(1), Varma N(3), Sachdeva MS(3), Bansal D(1),
Jain R(1), Naseem S(3).","Author information: 
(1)Paediatric Haematology-Oncology Unit, Post Graduate Institute of Medical
Education and Research, Chandigarh, India.
(2)Paediatric Haematology-Oncology Unit, Post Graduate Institute of Medical
Education and Research, Chandigarh, India. Electronic address:
bhatia.prateek@pgimer.edu.in.
(3)Department of Haematology, Post Graduate Institute of Medical Education and
Research, Chandigarh, India.","Copy number abnormalities (CNAs) and recurrent fusion transcripts are important
genetic events which define and prognosticate B-Cell Acute Lymphoblastic Leukemia
(B-ALL). We evaluated CNAs and fusion transcripts in 67 pediatric B-ALL cases and
correlated the data with standard risk factors and early treatment outcome
parameters. Common fusion transcripts ETV6-RUNX1, E2A-PBX, BCR-ABL1 and MLL-AF4
were examined by RT-PCR and noted in 15%, 15%, 13% and 1.4% of all cases
respectively. CNAs in IKZF1, PAX5, EBF1, BTG1, RB1, CDKN2A/B and genes from PAR1 
region viz., CSF2RA, IL3RA,P2RY8, SHOX region and CRLF2 were analyzed by
multiplex ligation dependent probe amplification assay and were detected in 70%
(47/67) of cases, with predominantly deletions in CDKN2A/B (36%), PAX5 (18%) and 
IKZF1 (16%). A statistically significant association of intermediate/poor risk
CNAs was noted with high WBC count (p = 0.001), NCI group (p = 0.02) and minimal 
residual disease at Day35 (p < 0.0001). IKZF1 and CDKN2A/B deletion revealed poor
EFS of 56% at 24 months as compared to EFS of 80% in rest of the cases (p = 0.05)
suggesting their potential role in early risk stratification.",Copyright © 2018 Elsevier Ltd. All rights reserved.,"DOI: 10.1016/j.leukres.2018.01.012 
PMID: 29407587  [Indexed for MEDLINE]"
11. Br J Haematol. 2018 Feb;180(4):550-562. doi: 10.1111/bjh.15056. Epub 2017 Nov 30.,"A risk score including microdeletions improves relapse prediction for standard
and medium risk precursor B-cell acute lymphoblastic leukaemia in children.","Sutton R(1)(2), Venn NC(1), Law T(1), Boer JM(3)(4), Trahair TN(1)(2)(5), Ng
A(6), Den Boer ML(3)(7), Dissanayake A(1), Giles JE(1), Dalzell P(8), Mayoh C(1),
Barbaric D(5), Revesz T(9), Alvaro F(10), Pieters R(4)(7), Haber M(1)(2), Norris 
MD(1)(11), Schrappe M(12), Dalla Pozza L(6), Marshall GM(1)(2)(5).","Author information: 
(1)Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Sydney,
Australia.
(2)School of Women's and Children's Health, UNSW, Sydney, Australia.
(3)Department of Paediatric Oncology/Haematology, Erasmus Medical Centre, Sophia 
Children's Hospital, Rotterdam, The Netherlands.
(4)Princess Máxima Centre for Paediatric Oncology, Utrecht, The Netherlands.
(5)Kids Cancer Centre, Sydney Children's Hospital, Randwick, Australia.
(6)Cancer Centre for Children, The Children's Hospital at Westmead, Westmead,
Australia.
(7)Dutch Childhood Oncology Group, The Hague, The Netherlands.
(8)SEALS Genetics, NSW Health Pathology, Randwick, Australia.
(9)Women's and Children's Hospital, SA Pathology, University of Adelaide,
Adelaide, Australia.
(10)John Hunter Children's Hospital, Newcastle, Australia.
(11)UNSW Centre for Childhood Cancer Research, Kensington, Australia.
(12)Christian-Albrechts-University Kiel and University Medical Centre
Schleswig-Holstein, Kiel, Germany.","To prevent relapse, high risk paediatric acute lymphoblastic leukaemia (ALL) is
treated very intensively. However, most patients who eventually relapse have
standard or medium risk ALL with low minimal residual disease (MRD) levels. We
analysed recurrent microdeletions and other clinical prognostic factors in a
cohort of 475 uniformly treated non-high risk precursor B-cell ALL patients with 
the aim of better predicting relapse and refining risk stratification. Lower
relapse-free survival at 7 years (RFS) was associated with IKZF1 intragenic
deletions (P < 0·0001); P2RY8-CRLF2 gene fusion (P < 0·0004); Day 33 MRD>5 × 10-5
(P < 0·0001) and High National Cancer Institute (NCI) risk (P < 0·0001). We
created a predictive model based on a risk score (RS) for deletions, MRD and NCI 
risk, extending from an RS of 0 (RS0) for patients with no unfavourable factors
to RS2 +  for patients with 2 or 3 high risk factors. RS0, RS1, and RS2 +  groups
had RFS of 93%, 78% and 49%, respectively, and overall survival (OS) of 99%, 91% 
and 71%. The RS provided greater discrimination than MRD-based risk
stratification into standard (89% RFS, 96% OS) and medium risk groups (79% RFS,
91% OS). We conclude that this RS may enable better early therapeutic
stratification and thus improve cure rates for childhood ALL.",© 2017 John Wiley & Sons Ltd.,"DOI: 10.1111/bjh.15056 
PMID: 29194562  [Indexed for MEDLINE]"
12. Am J Clin Pathol. 2017 Nov 20;148(6):523-528. doi: 10.1093/ajcp/aqx111.,"Philadelphia Chromosome-like Mixed-Phenotype Acute Leukemia Demonstrating
P2RY8-CRLF2 Fusion and JAK1 Mutation.","Choi SM(1), Frederiksen JK(1), Ross CW(1), Bixby DL(2), Shao L(1).","Author information: 
(1)Departments of Pathology.
(2)Internal Medicine, University of Michigan, Ann Arbor.","Objectives: Philadelphia chromosome-like (Ph-like) genetic alterations define a
subset of B lymphoblastic leukemia/lymphoma (B-ALL), which represents a separate 
provisional entity in the World Health Organization 2016 updated classification. 
However, these alterations have not been described outside the context of B-ALL.
Methods: Cytogenomic array and molecular analysis identified a Ph-like signature 
in a mixed-phenotype acute leukemia (MPAL), B/myeloid, confirmed using
conventional immunophenotypic and cytochemical analysis.
Results: Flow cytometry identified a blast population demonstrating a B-cell
lineage and myeloperoxidase positivity. A P2RY8-CRLF2 fusion and JAK1 mutation
were detected, both of which are associated with Ph-like features.
Conclusions: To our knowledge, this is the first report of Ph-like MPAL, which
may represent a new diagnostic entity. We emphasize the need for refinement of
diagnostic criteria for MPALs and highlight an opportunity for expansion of
inclusion criteria in ongoing clinical trials studying the use of tyrosine kinase
inhibitor therapy to include cases of Ph-like MPAL.","© American Society for Clinical Pathology, 2017. All rights reserved. For
permissions, please e-mail: journals.permissions@oup.com","DOI: 10.1093/ajcp/aqx111 
PMID: 29140408  [Indexed for MEDLINE]"
"13. Cancer Lett. 2017 Nov 1;408:92-101. doi: 10.1016/j.canlet.2017.08.034. Epub 2017 
Sep 1.","Differential expression of MUC4, GPR110 and IL2RA defines two groups of
CRLF2-rearranged acute lymphoblastic leukemia patients with distinct secondary
lesions.","Sadras T(1), Heatley SL(1), Kok CH(1), Dang P(2), Galbraith KM(2), McClure BJ(2),
Muskovic W(3), Venn NC(3), Moore S(4), Osborn M(5), Revesz T(6), Moore AS(7),
Hughes TP(8), Yeung D(9), Sutton R(10), White DL(11).","Author information: 
(1)Cancer Theme, South Australian Health & Medical Research Institute, Adelaide, 
SA, Australia; Discipline of Medicine, University of Adelaide, Adelaide, SA,
Australia.
(2)Cancer Theme, South Australian Health & Medical Research Institute, Adelaide, 
SA, Australia.
(3)Molecular Diagnostics Program, Children's Cancer Institute, Lowy Cancer
Research Centre, UNSW Sydney, NSW, Australia.
(4)Department of Genetic Pathology, SA Pathology, Adelaide, SA, Australia.
(5)SA Pathology at Women's & Children's Hospital, Adelaide, SA, Australia;
Australian Genomic Health Alliance, Adelaide, SA, Australia.
(6)SA Pathology at Women's & Children's Hospital, Adelaide, SA, Australia.
(7)The University of Queensland Diamantina Institute, UQ Child Health Research
Centre, The University of Queensland, Brisbane, QLD, Australia; Oncology Services
Group, Children's Health Queensland Hospital and Health Service, Brisbane, QLD,
Australia.
(8)Cancer Theme, South Australian Health & Medical Research Institute, Adelaide, 
SA, Australia; Discipline of Medicine, University of Adelaide, Adelaide, SA,
Australia; Department of Haematology, SA Pathology, Adelaide, SA, Australia.
(9)Department of Haematology, SA Pathology, Adelaide, SA, Australia.
(10)Molecular Diagnostics Program, Children's Cancer Institute, Lowy Cancer
Research Centre, UNSW Sydney, NSW, Australia; Australian Genomic Health Alliance,
Adelaide, SA, Australia; School of Women's and Children's Health, Medicine,
University of NSW, Sydney, NSW, Australia.
(11)Cancer Theme, South Australian Health & Medical Research Institute, Adelaide,
SA, Australia; Discipline of Medicine, University of Adelaide, Adelaide, SA,
Australia; Australian Genomic Health Alliance, Adelaide, SA, Australia.
Electronic address: deborah.white@sahmri.com.","CRLF2-rearrangements (CRLF2-r) occur frequently in Ph-like B-ALL, a high-risk ALL
sub-type characterized by a signaling profile similar to Ph + ALL, however
accumulating evidence indicates genetic heterogeneity within CRLF2-r ALL. We
performed thorough genomic characterization of 35 CRLF2-r cases (P2RY8-CRLF2
n = 18; IGH-CRLF2 n = 17). Activating JAK2 mutations were present in 34% of
patients, and a CRLF2-F232C mutation was identified in an additional 17%. IKZF1
deletions were detected in 63% of cases. The majority of patients (26/35)
classified as Ph-like, and these were characterized by significantly higher
levels of MUC4, GPR110 and IL2RA/CD25. In addition, Ph-like CRLF2-r samples were 
significantly enriched for IKZF1 deletions, JAK2/CRLF2 mutations and increased
expression of JAK/STAT target genes (CISH, SOCS1), suggesting that
mutation-driven CRLF2/JAK2 activation is more frequent in this sub-group. Less is
known about the genomics of CRLF2-r cases lacking JAK2-pathway mutations, but
KRAS/NRAS mutations were identified in 4/9 non-Ph-like samples. This work
highlights the heterogeneity of secondary lesions which may arise and influence
intracellular-pathway activation in CRLF2-r patients, and importantly presents
distinct therapeutic targets within a group of patients harboring identical
primary translocations, for whom efficient directed therapies are currently
lacking.",Copyright © 2017 Elsevier B.V. All rights reserved.,"DOI: 10.1016/j.canlet.2017.08.034 
PMID: 28866095  [Indexed for MEDLINE]"
"14. Genes Chromosomes Cancer. 2017 Oct;56(10):730-749. doi: 10.1002/gcc.22477. Epub
2017 Jul 1.","Copy number alterations determined by single nucleotide polymorphism array
testing in the clinical laboratory are indicative of gene fusions in pediatric
cancer patients.","Busse TM(1), Roth JJ(2), Wilmoth D(3), Wainwright L(3), Tooke L(3), Biegel
JA(1)(4).","Author information: 
(1)Department of Pathology and Laboratory Medicine Children's Hospital of Los
Angeles, Center for Personalized Medicine, Los Angeles, California.
(2)Department of Pathology and Laboratory Medicine, Hospital of the University of
Pennsylvania, Philadelphia, Pennsylvania.
(3)Department of Pathology and Laboratory Medicine, The Children's Hospital of
Philadelphia, Philadelphia, Pennsylvania.
(4)Department of Pathology, USC Keck School of Medicine, Los Angeles, California.","Gene fusions resulting from structural rearrangements are an established
mechanism of tumorigenesis in pediatric cancer. In this clinical cohort, 1,350
single nucleotide polymorphism (SNP)-based chromosomal microarrays from 1,211
pediatric cancer patients were evaluated for copy number alterations (CNAs)
associated with gene fusions. Karyotype or fluorescence in situ hybridization
studies were performed in 42% of the patients. Ten percent of the bone marrow or 
solid tumor specimens had SNP array-associated CNAs suggestive of a gene fusion. 
Alterations involving ETV6, ABL1-NUP214, EBF1-PDGFRB, KMT2A(MLL), LMO2-RAG,
MYH11-CBFB, NSD1-NUP98, PBX1, STIL-TAL1, ZNF384-TCF3, P2RY8-CRLF2, and
RUNX1T1-RUNX1 fusions were detected in the bone marrow samples. The most common
alteration among the low-grade gliomas was a 7q34 tandem duplication resulting in
a KIAA1549-BRAF fusion. Additional fusions identified in the pediatric brain
tumors included FAM131B-BRAF and RAF1-QKI. COL1A1-PDGFB, CRTC1-MAML2, EWSR1,
HEY1, PAX3- and PAX7-FOXO1, and PLAG1 fusions were determined in a variety of
solid tumors and a novel potential gene fusion, FGFR1-USP6, was detected in an
aneurysmal bone cyst. The identification of these gene fusions was instrumental
in tumor diagnosis. In contrast to hematologic and solid tumors in adults that
are predominantly driven by mutations, the majority of hematologic and solid
tumors in children are characterized by CNAs and gene fusions. Chromosomal
microarray analysis is therefore a robust platform to identify diagnostic and
prognostic markers in the clinical setting.","© 2017 Wiley Periodicals, Inc.","DOI: 10.1002/gcc.22477 
PMID: 28597942  [Indexed for MEDLINE]"
"15. Blood. 2017 Jun 22;129(25):3352-3361. doi: 10.1182/blood-2016-12-758979. Epub
2017 Apr 13.","Targetable kinase gene fusions in high-risk B-ALL: a study from the Children's
Oncology Group.","Reshmi SC(1)(2), Harvey RC(3), Roberts KG(4), Stonerock E(1), Smith A(5), Jenkins
H(1), Chen IM(3), Valentine M(6), Liu Y(7), Li Y(7), Shao Y(4), Easton J(7),
Payne-Turner D(4), Gu Z(4), Tran TH(8), Nguyen JV(8), Devidas M(9), Dai Y(9),
Heerema NA(2), Carroll AJ 3rd(10), Raetz EA(11), Borowitz MJ(12), Wood BL(13),
Angiolillo AL(14), Burke MJ(15), Salzer WL(16), Zweidler-McKay PA(17), Rabin
KR(18), Carroll WL(19), Zhang J(7), Loh ML(8), Mullighan CG(4), Willman CL(3),
Gastier-Foster JM(1)(2)(20), Hunger SP(21).","Author information: 
(1)Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH.
(2)Department of Pathology, The Ohio State University College of Medicine,
Columbus, OH.
(3)University of New Mexico Cancer Center, Albuquerque, NM.
(4)Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN.
(5)Comprehensive Cancer Center, The Ohio State University College of Medicine,
Columbus, OH.
(6)Department of Cytogenetics and.
(7)Department of Computational Biology, St. Jude Children's Research Hospital,
Memphis, TN.
(8)Department of Pediatrics, UCSF Benioff Children's Hospital and Helen Diller
Family Comprehensive Cancer Center, University of California, San Francisco, San 
Francisco, CA.
(9)Department of Biostatistics, University of Florida, Gainesville, FL.
(10)Department of Genetics, University of Alabama at Birmingham, Birmingham, AL.
(11)Department of Pediatrics, University of Utah, Salt Lake City, UT.
(12)Department of Pathology, Johns Hopkins University, Baltimore, MD.
(13)Seattle Children's Hospital, Seattle, WA.
(14)Children's National Medical Center, Washington, DC.
(15)Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI.
(16)US Army Medical Research and Materiel Command, Fort Detrick, MD.
(17)Department of Pediatrics, MD Anderson Cancer Center, Houston, TX.
(18)Department of Pediatrics, Baylor College of Medicine, Houston, TX.
(19)Perlmutter Cancer Center, NYU Langone Medical Center, New York, NY.
(20)Department of Pediatrics, The Ohio State University College of Medicine,
Columbus, OH; and.
(21)Department of Pediatrics, Children's Hospital of Philadelphia and Perelman
School of Medicine, University of Pennsylvania, Philadelphia, PA.","Comment in
    Blood. 2017 Jun 22;129(25):3280-3282.","Philadelphia chromosome-like (Ph-like) acute lymphoblastic leukemia (ALL) is a
high-risk subtype characterized by genomic alterations that activate cytokine
receptor and kinase signaling. We examined the frequency and spectrum of
targetable genetic lesions in a retrospective cohort of 1389 consecutively
diagnosed patients with childhood B-lineage ALL with high-risk clinical features 
and/or elevated minimal residual disease at the end of remission induction
therapy. The Ph-like gene expression profile was identified in 341 of 1389
patients, 57 of whom were excluded from additional analyses because of the
presence of BCR-ABL1 (n = 46) or ETV6-RUNX1 (n = 11). Among the remaining 284
patients (20.4%), overexpression and rearrangement of CRLF2 (IGH-CRLF2 or
P2RY8-CRLF2) were identified in 124 (43.7%), with concomitant genomic alterations
activating the JAK-STAT pathway (JAK1, JAK2, IL7R) identified in 63 patients
(50.8% of those with CRLF2 rearrangement). Among the remaining patients, using
reverse transcriptase polymerase chain reaction or transcriptome sequencing, we
identified targetable ABL-class fusions (ABL1, ABL2, CSF1R, and PDGFRB) in 14.1%,
EPOR rearrangements or JAK2 fusions in 8.8%, alterations activating other
JAK-STAT signaling genes (IL7R, SH2B3, JAK1) in 6.3% or other kinases (FLT3,
NTRK3, LYN) in 4.6%, and mutations involving the Ras pathway (KRAS, NRAS, NF1,
PTPN11) in 6% of those with Ph-like ALL. We identified 8 new rearrangement
partners for 4 kinase genes previously reported to be rearranged in Ph-like ALL. 
The current findings provide support for the precision-medicine testing and
treatment approach for Ph-like ALL implemented in Children's Oncology Group ALL
trials.","DOI: 10.1182/blood-2016-12-758979 
PMCID: PMC5482101
PMID: 28408464  [Indexed for MEDLINE]"
"16. Genes Chromosomes Cancer. 2017 Aug;56(8):608-616. doi: 10.1002/gcc.22464. Epub
2017 May 5.","ETV6/RUNX1-like acute lymphoblastic leukemia: A novel B-cell precursor leukemia
subtype associated with the CD27/CD44 immunophenotype.","Zaliova M(1)(2)(3), Kotrova M(1)(2)(3), Bresolin S(4), Stuchly J(1)(2), Stary
J(2)(3), Hrusak O(1)(2)(3), Te Kronnie G(4), Trka J(1)(2)(3), Zuna J(1)(2)(3),
Vaskova M(1)(2).","Author information: 
(1)CLIP-Childhood Leukaemia Investigation Prague, Czech Republic.
(2)Department of Paediatric Haematology and Oncology, Second Faculty of Medicine,
Charles University, Prague, Czech Republic.
(3)University Hospital Motol, Prague, Czech Republic.
(4)Department of Women's and Children's Health, University of Padova, Italy.","We have shown previously that ETV6/RUNX1-positive acute lymphoblastic leukemia
(ALL) is distinguishable from other ALL subtypes by CD27pos /CD44low-neg
immunophenotype. During diagnostic immunophenotyping of 573 childhood B-cell
precursor ALL (BCP-ALL), we identified eight cases with this immunophenotype
among ""B-other ALL"" (BCP-ALL cases negative for routinely tested
chromosomal/genetic aberrations). We aimed to elucidate whether these cases
belong to the recently described ETV6/RUNX1-like ALL defined by the
ETV6/RUNX1-specific gene expression profile (GEP), harboring concurrent ETV6 and 
IKZF1 lesions. We performed comprehensive genomic analysis using single
nucleotide polymorphism arrays, whole exome and transcriptome sequencing and GEP 
on microarrays. In unsupervised hierarchical clustering based on GEP, five out of
seven analyzed CD27pos /CD44low-neg B-other cases clustered with
ETV6/RUNX1-positive ALL and were thus classified as ETV6/RUNX1-like ALL. The two 
cases clustering outside ETV6/RUNX1-positive ALL harbored a P2RY8/CRLF2 fusion
with activating JAK2 mutations and a TCF3/ZNF384 fusion, respectively, assigning 
them to other ALL subtypes. All five ETV6/RUNX1-like cases harbored ETV6
deletions; uniform intragenic ARPP21 deletions and various IKZF1 lesions were
each found in three ETV6/RUNX1-like cases. The frequency of ETV6 and ARPP21
deletions was significantly higher in ETV6/RUNX1-like ALL compared with a
reference cohort of 42 B-other ALL. In conclusion, we show that ETV6/RUNX1-like
ALL is associated with CD27pos /CD44low-neg immunophenotype and identify ARPP21
deletions to contribute to its specific genomic profile enriched for ETV6 and
IKZF1 lesions. In conjunction with previously published data, our study
identifies the ETV6 lesion as the only common genetic aberration and thus the
most likely key driver of ETV6/RUNX1-like ALL.","© 2017 Wiley Periodicals, Inc.","DOI: 10.1002/gcc.22464 
PMID: 28395118  [Indexed for MEDLINE]"
17. Pediatr Blood Cancer. 2017 Oct;64(10). doi: 10.1002/pbc.26539. Epub 2017 Apr 1.,"Molecular characterization of acute lymphoblastic leukemia with high CRLF2 gene
expression in childhood.","Schmäh J(1), Fedders B(1), Panzer-Grümayer R(2), Fischer S(2), Zimmermann M(3),
Dagdan E(3), Bens S(4)(5), Schewe D(1), Moericke A(1), Alten J(1), Bleckmann
K(1), Siebert R(4)(5), Schrappe M(1), Stanulla M(3), Cario G(1).","Author information: 
(1)Department of Pediatrics, University Medical Center Schleswig-Holstein, Kiel, 
Germany.
(2)Children's Cancer Research Institute, St. Anna Kinderkrebsforschung, Vienna,
Austria.
(3)Department of Pediatric Hematology and Oncology, Hannover Medical School,
Hannover, Germany.
(4)Institute of Human Genetics, Christian-Albrechts-University Kiel & University 
Medical Center Schleswig-Holstein, Kiel, Germany.
(5)Institute of Human Genetics, University of Ulm, Ulm, Germany.","BACKGROUND: A high-level expression of the CRLF2 gene is frequent in precursor
B-cell acute lymphoblastic leukemia (pB-ALL) and can be caused by different
genetic aberrations. The presence of the most frequent alteration, the
P2RY8/CRLF2 fusion, was shown to be associated with a high relapse incidence in
children treated according to ALL-Berlin-Frankfurt-Münster (BFM) protocols, which
is poorly understood. Moreover, the frequency of other alterations has not been
systematically analyzed yet.
PROCEDURE: CRLF2 mRNA expression and potential genetic aberrations causing a
CRLF2 high expression were prospectively assessed in 1,105 patients treated
according to the Associazione Italiana Ematologia Oncologia Pediatrica
(AIEOP)-BFM ALL 2009 protocol. Additionally, we determined copy number
alterations in selected B-cell differentiation genes for all CRLF2
high-expressing pB-ALL cases, as well as JAK2 and CRLF2 mutations.
RESULTS: A CRLF2 high expression was detected in 26/178 (15%) T-cell acute
lymphoblastic leukemia (T-ALL) cases, 21 of them (81%) had been stratified as
high-risk patients by treatment response. In pB-ALL, a CRLF2 high expression was 
determined in 91/927 (10%) cases; the P2RY8/CRLF2 rearrangement in 44/91 (48%) of
them, supernumerary copies of CRLF2 in 18/91 (20%), and, notably, the IGH/CRLF2
translocation was detected in 16/91 (18%). Remarkably, 7 of 16 (44%) patients
with IGH/CRLF2 translocation had already relapsed. P2RY8/CRLF2- and
IGH/CRLF2-positive samples (70 and 94%, respectively) were characterized by a
high frequency of additional deletions in B-cell differentiation genes such as
IKZF1 or PAX5.
CONCLUSION: Our data suggest that this high frequency of genetic aberrations in
the context of a high CRLF2 expression could contribute to the high risk of
relapse in P2RY8/CRLF2- and IGH/CRLF2-positive ALL.","© 2017 Wiley Periodicals, Inc.","DOI: 10.1002/pbc.26539 
PMID: 28371317  [Indexed for MEDLINE]"
"18. Genes Chromosomes Cancer. 2017 May;56(5):363-372. doi: 10.1002/gcc.22439. Epub
2017 Jan 18.","Characterisation of the genomic landscape of CRLF2-rearranged acute lymphoblastic
leukemia.","Russell LJ(1), Jones L(1), Enshaei A(1), Tonin S(1), Ryan SL(1), Eswaran J(1),
Nakjang S(2), Papaemmanuil E(3)(4), Tubio JM(4), Fielding AK(5), Vora A(6),
Campbell PJ(4), Moorman AV(1), Harrison CJ(1).","Author information: 
(1)Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research,
Newcastle University, Newcastle-upon-Tyne, UK.
(2)Bioinformatics Support Unit, Newcastle University, Newcastle-upon-Tyne, UK.
(3)Department of Epidemiology-Biostatistics, Memorial Sloan Kettering Cancer
Center, USA.
(4)Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
(5)Research Department of Haemaoloty, UCL Cancer Institute, London, UK.
(6)Department of Haematology, Sheffield Children's Hospital, Sheffield, UK.","Deregulated expression of the type I cytokine receptor, CRLF2, is observed in
5-15% of precursor B-cell acute lymphoblastic leukaemia (B-ALL). We aimed to
determine the clinical and genetic landscape of those with IGH-CRLF2 or
P2RY8-CRLF2 (CRLF2-r) using multiple genomic approaches. Clinical and demographic
features of CRLF2-r patients were characteristic of B-ALL. Patients with
IGH-CRLF2 were older (14 y vs. 4 y, P < .001), while the incidence of CRLF2-r
among Down syndrome patients was high (50/161, 31%). CRLF2-r co-occurred with
primary chromosomal rearrangements but the majority (111/161, 69%) had B-other
ALL. Copy number alteration (CNA) profiles were similar to B-other ALL, although 
CRLF2-r patients harbored higher frequencies of IKZF1 (60/138, 43% vs. 77/1351,
24%) and BTG1 deletions (20/138, 15% vs. 3/1351, 1%). There were significant
differences in CNA profiles between IGH-CRLF2 and P2RY8-CRLF2 patients: IKZF1
(25/35, 71% vs. 36/108, 33%, P < .001), BTG1 (11/35, 31% vs. 10/108, 9%, P
=.004), and ADD3 deletions (9/19, 47% vs. 5/38, 13%, P =.008). A novel gene
fusion, USP9X-DDX3X, was discovered in 10/54 (19%) of patients. Pathway analysis 
of the mutational profile revealed novel involvement for focal adhesion. Although
the functional relevance of many of these abnormalities are unknown, they likely 
activate additional pathways, which may represent novel therapeutic targets.","© 2017 The Authors Genes, Chromosomes and Cancer Published byWiley Periodicals,
Inc.","DOI: 10.1002/gcc.22439 
PMCID: PMC5396319
PMID: 28033648  [Indexed for MEDLINE]"
"19. PLoS Med. 2016 Dec 13;13(12):e1002197. doi: 10.1371/journal.pmed.1002197.
eCollection 2016 Dec.","Histological Transformation and Progression in Follicular Lymphoma: A Clonal
Evolution Study.","Kridel R(1), Chan FC(1)(2), Mottok A(1)(3), Boyle M(1), Farinha P(1), Tan K(1),
Meissner B(1), Bashashati A(4), McPherson A(4), Roth A(2)(4), Shumansky K(4), Yap
D(4), Ben-Neriah S(1), Rosner J(4), Smith MA(2)(4), Nielsen C(4), Giné E(1),
Telenius A(1), Ennishi D(1), Mungall A(5), Moore R(5), Morin RD(5)(6), Johnson
NA(7), Sehn LH(1), Tousseyn T(8)(9), Dogan A(10)(11), Connors JM(1), Scott DW(1),
Steidl C(1)(3), Marra MA(5), Gascoyne RD(1)(3), Shah SP(3)(4).","Author information: 
(1)Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, British Columbia,
Canada.
(2)Bioinformatics Graduate Program, University of British Columbia, Vancouver,
British Columbia, Canada.
(3)Department of Pathology and Laboratory Medicine, University of British
Columbia, Vancouver, British Columbia, Canada.
(4)Department of Molecular Oncology, BC Cancer Agency, Vancouver, British
Columbia, Canada.
(5)Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British
Columbia, Canada.
(6)Department of Molecular Biology and Biochemistry, Simon Fraser University,
Burnaby, British Columbia, Canada.
(7)Jewish General Hospital, Montreal, Quebec, Canada.
(8)Translational Cell and Tissue Research Lab, Department for Imaging and
Pathology, University of Leuven (KU Leuven), Leuven, Belgium.
(9)Department of Pathology, Universitaire Ziekenhuizen Leuven (UZ Leuven),
Leuven, Belgium.
(10)Department of Laboratory and Pathology, Mayo Clinic, Rochester, Minnesota,
United States of America.
(11)Departments of Pathology and Laboratory Medicine, Memorial Sloan Kettering
Cancer Center, New York, New York, United States of America.","BACKGROUND: Follicular lymphoma (FL) is an indolent, yet incurable B cell
malignancy. A subset of patients experience an increased mortality rate driven by
two distinct clinical end points: histological transformation and early
progression after immunochemotherapy. The nature of tumor clonal dynamics leading
to these clinical end points is poorly understood, and previously determined
genetic alterations do not explain the majority of transformed cases or
accurately predict early progressive disease. We contend that detailed knowledge 
of the expansion patterns of specific cell populations plus their associated
mutations would provide insight into therapeutic strategies and disease biology
over the time course of FL clinical histories.
METHODS AND FINDINGS: Using a combination of whole genome sequencing, targeted
deep sequencing, and digital droplet PCR on matched diagnostic and relapse
specimens, we deciphered the constituent clonal populations in 15 transformation 
cases and 6 progression cases, and measured the change in clonal population
abundance over time. We observed widely divergent patterns of clonal dynamics in 
transformed cases relative to progressed cases. Transformation specimens were
generally composed of clones that were rare or absent in diagnostic specimens,
consistent with dramatic clonal expansions that came to dominate the
transformation specimens. This pattern was independent of time to transformation 
and treatment modality. By contrast, early progression specimens were composed of
clones that were already present in the diagnostic specimens and exhibited only
moderate clonal dynamics, even in the presence of immunochemotherapy. Analysis of
somatic mutations impacting 94 genes was undertaken in an extension cohort
consisting of 395 samples from 277 patients in order to decipher disrupted
biology in the two clinical end points. We found 12 genes that were more commonly
mutated in transformed samples than in the preceding FL tumors, including TP53,
B2M, CCND3, GNA13, S1PR2, and P2RY8. Moreover, ten genes were more commonly
mutated in diagnostic specimens of patients with early progression, including
TP53, BTG1, MKI67, and XBP1.
CONCLUSIONS: Our results illuminate contrasting modes of evolution shaping the
clinical histories of transformation and progression. They have implications for 
interpretation of evolutionary dynamics in the context of treatment-induced
selective pressures, and indicate that transformation and progression will
require different clinical management strategies.","DOI: 10.1371/journal.pmed.1002197 
PMCID: PMC5154502
PMID: 27959929  [Indexed for MEDLINE]","Conflict of interest statement: I have read the journal's policy and the authors 
of this manuscript have the following competing interests: SPS is a founder and
shareholder of Contextual Genomics Inc., developer of clinical genomic tests for 
cancer."
20. Leukemia. 2017 Jul;31(7):1491-1501. doi: 10.1038/leu.2016.365. Epub 2016 Nov 30.,"Genomic and transcriptional landscape of P2RY8-CRLF2-positive childhood acute
lymphoblastic leukemia.","Vesely C(1), Frech C(1), Eckert C(2), Cario G(3), Mecklenbräuker A(1), Zur Stadt 
U(4), Nebral K(1), Kraler F(1), Fischer S(1), Attarbaschi A(5), Schuster M(6),
Bock C(6), Cavé H(7), von Stackelberg A(2), Schrappe M(3), Horstmann MA(4), Mann 
G(5), Haas OA(1)(5), Panzer-Grümayer R(1).","Author information: 
(1)Children's Cancer Research Institute (CCRI), Leukemia Biology Group, Vienna,
Austria.
(2)Department of Pediatric Oncology/Hematology, Charité Universitätsmedizin
Berlin, Campus Virchow Klinikum, Berlin, Germany.
(3)Department of Pediatrics, Medical University of Schleswig Holstein, Kiel,
Germany.
(4)Clinic of Pediatric Hematology and Oncology, University Medical Center
Hamburg-Eppendorf, Hamburg, Germany.
(5)St Anna Kinderspital, Medical University Vienna, Vienna, Austria.
(6)Research Center for Molecular Medicine (CeMM), Vienna, Austria.
(7)UFR de Médecine Paris-Diderot, INSERM UMR_S1131-Institute Universitaire
d'hématologie, Département de Génétique-UF de Génétique Moléculaire, Hôpital
Robert Debré, Paris, France.","Children with P2RY8-CRLF2-positive acute lymphoblastic leukemia have an increased
relapse risk. Their mutational and transcriptional landscape, as well as the
respective patterns at relapse remain largely elusive. We, therefore, performed
an integrated analysis of whole-exome and RNA sequencing in 41 major clone
fusion-positive cases including 19 matched diagnosis/relapse pairs. We detected a
variety of frequently subclonal and highly instable JAK/STAT but also RTK/Ras
pathway-activating mutations in 76% of cases at diagnosis and virtually all
relapses. Unlike P2RY8-CRLF2 that was lost in 32% of relapses, all other genomic 
alterations affecting lymphoid development (58%) and cell cycle (39%) remained
stable. Only IKZF1 alterations predominated in relapsing cases (P=0.001) and
increased from initially 36 to 58% in matched cases. IKZF1's critical role is
further corroborated by its specific transcriptional signature comprising stem
cell features with signs of impaired lymphoid differentiation, enhanced focal
adhesion, activated hypoxia pathway, deregulated cell cycle and increased drug
resistance. Our findings support the notion that P2RY8-CRLF2 is dispensable for
relapse development and instead highlight the prominent rank of IKZF1 for relapse
development by mediating self-renewal and homing to the bone marrow niche.
Consequently, reverting aberrant IKAROS signaling or its disparate programs
emerges as an attractive potential treatment option in these leukemias.","DOI: 10.1038/leu.2016.365 
PMCID: PMC5508072
PMID: 27899802  [Indexed for MEDLINE]",
"
1. Leuk Lymphoma. 2017 Apr;58(4):950-958. doi: 10.1080/10428194.2016.1219902. Epub
2016 Nov 17.","Diagnostic evaluation of RNA sequencing for the detection of genetic
abnormalities associated with Ph-like acute lymphoblastic leukemia (ALL).","Yap KL(1), Furtado LV(2), Kiyotani K(1), Curran E(1), Stock W(1), McNeer JL(3),
Kadri S(2), Segal JP(2), Nakamura Y(1), Le Beau MM(1), Gurbuxani S(2), Raca G(1).","Author information: 
(1)a Department of Medicine, Section of Hematology/Oncology , The University of
Chicago , Chicago , IL , USA.
(2)b Department of Pathology , The University of Chicago , Chicago , IL , USA.
(3)c Department of Pediatrics, Section of Pediatric Hematology/Oncology , The
University of Chicago , Chicago , IL , USA.","Philadelphia (Ph)-like acute lymphoblastic leukemia (ALL) is a molecular subtype 
of high-risk B-cell ALL characterized by formation of abnormal gene fusions
involving tyrosine kinase (TK) and cytokine receptor genes and activation of TK
signaling. Because of the diversity of associated genetic changes, the detection 
of Ph-like ALL cases currently requires multiple cytogenetic and molecular
assays; thus, our goal was to develop a consolidated workflow for detecting
genetic abnormalities in Ph-like ALL. We found that total and targeted RNA
sequencing (RNAseq)-based approach allowed the detection of abnormal fusion
transcripts (EBF1-PDGFRB, P2RY8-CRLF2, RCSD1-ABL1, and RCSD1-ABL2). The
bioinformatics algorithm accurately detected the fusion transcripts without prior
input about possible events. Additionally, we showed that RNAseq analysis enabled
evaluation for disease-associated sequence variants in expressed transcripts.
While total RNAseq can be a second tier approach allowing discovery of novel
genetic alterations, the targeted RNAseq workflow offers a clinically applicable 
method for the detection of fusion transcripts.","DOI: 10.1080/10428194.2016.1219902 
PMCID: PMC6077981
PMID: 27855558  [Indexed for MEDLINE]"
2. Oncotarget. 2016 Dec 6;7(49):80664-80679. doi: 10.18632/oncotarget.13025.,"Integrative analysis of DNA copy number, DNA methylation and gene expression in
multiple myeloma reveals alterations related to relapse.","Krzeminski P(1)(2), Corchete LA(1), García JL(2), López-Corral L(1)(2), Fermiñán 
E(3), García EM(3), Martín AA(1), Hernández-Rivas JM(1)(2), García-Sanz R(1)(2), 
San Miguel JF(4), Gutiérrez NC(1)(2).","Author information: 
(1)Departamento de Hematología, Hospital Universitario, IBSAL, IBMCC (USAL-CSIC),
Salamanca, Spain.
(2)Centro de Investigación del Cáncer-IBMCC (USAL-CSIC), Salamanca, Spain.
(3)Unidad de Genómica y Proteómica, Centro de Investigación del Cáncer-IBMCC
(USAL-CSIC), Salamanca, Spain.
(4)Clínica Universidad de Navarra, Centro de Investigaciones Médicas Aplicadas
(CIMA), Pamplona, Spain.","Multiple myeloma (MM) remains incurable despite the introduction of novel agents,
and a relapsing course is observed in most patients. Although the development of 
genomic technologies has greatly improved our understanding of MM pathogenesis,
the mechanisms underlying relapse have been less thoroughly investigated. In this
study, an integrative analysis of DNA copy number, DNA methylation and gene
expression was conducted in matched diagnosis and relapse samples from MM
patients. Overall, the acquisition of abnormalities at relapse was much more
frequent than the loss of lesions present at diagnosis, and DNA losses were
significantly more frequent in relapse than in diagnosis samples. Interestingly, 
copy number abnormalities involving more than 100 Mb of DNA at relapse
significantly affect the gene expression of these samples, provoking a particular
deregulation of the IL-8 pathway. On the other hand, no significant modifications
of gene expression were observed in those samples with less than 100 Mb affected 
by chromosomal changes. Although several statistical approaches were used to
identify genes whose abnormal expression at relapse was regulated by methylation,
only two genes that were significantly deregulated in relapse samples (SORL1 and 
GLT1D1) showed a negative correlation between methylation and expression. Further
analysis revealed that DNA methylation was involved in regulating SORL1
expression in MM. Finally, relevant changes in gene expression observed in
relapse samples, such us downregulation of CD27 and P2RY8, were most likely not
preceded by alterations in the corresponding DNA. Taken together, these results
suggest that the genomic heterogeneity described at diagnosis remains at relapse.","DOI: 10.18632/oncotarget.13025 
PMCID: PMC5348347
PMID: 27811368  [Indexed for MEDLINE]"
"3. Genes Chromosomes Cancer. 2017 Feb;56(2):135-146. doi: 10.1002/gcc.22421. Epub
2016 Nov 5.","Prognostic significance of P2RY8-CRLF2 and CRLF2 overexpression may vary across
risk subgroups of childhood B-cell acute lymphoblastic leukemia.","Dou H(1)(2), Chen X(3), Huang Y(4), Su Y(5), Lu L(6), Yu J(5), Yin Y(1)(2)(7),
Bao L(3)(8).","Author information: 
(1)Department of Clinical Laboratory, Ministry of Education Key Laboratory of
Child Development and Disorders, Children's Hospital of Chongqing Medical
University, Chongqing, China.
(2)Key Laboratory of Pediatrics in Chongqing, Chongqing International Science and
Technology Cooperation Center for Child Development and Disorders, Children's
Hospital of Chongqing Medical University, Chongqing, China.
(3)Center for Clinical Molecular Medicine, Ministry of Education Key Laboratory
of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics,
Children's Hospital of Chongqing Medical University, Chongqing, China.
(4)Research Center for Immunity and Infectious Diseases, Ministry of Education
Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of
Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing,
China.
(5)Department of Hematology and Oncology, Ministry of Education Key Laboratory of
Child Development and Disorders, Chongqing Key Laboratory of Pediatrics,
Children's Hospital of Chongqing Medical University, Chongqing, China.
(6)Department of Rheumatology, Huashan Hospital, Fudan University, Shanghai,
China.
(7)Ministry of Education Key Laboratory of Clinical Laboratory Diagnostics,
College of Laboratory Medicine, Chongqing Medical University, Chongqing, China.
(8)Department of Pathology and Laboratory Medicine, Geisel School of Medicine
Dartmouth College, New Hampshire, USA.","The cytokine receptor-like factor 2 (CRLF2) gene plays an important role in early
B-cell development. Aberrations in CRLF2 activate the JAK-STAT signaling pathway 
that contributes to B-cell acute lymphoblastic leukemia (B-ALL). The prognostic
significance of CRLF2 overexpression and P2RY8-CRLF2 fusion in various B-ALL risk
subgroups has not been well established. Two hundred seventy-one patients with
newly diagnosed childhood B-ALL were enrolled from a Chinese population. The
prevalence of CRLF2 overexpression, CRLF2-P2RY8 fusion, CRLF2 F232C mutation, and
JAK2 and IL7R mutational status were analyzed, and the prognostic impact of CRLF2
overexpression and P2RY8-CRLF2 on B-ALL was evaluated by assessing their
influence on overall survival and event-free survival. CRLF2 overexpression and
P2RY8-CRLF2 were found in 19% and 10%, respectively, in the whole cohort. No
correlation between CRLF2 overexpression and P2RY8-CRLF2 was observed. CRLF2
F322C and IL7R mutations were not detected in B-ALL cases overexpressing CRLF2,
and no JAK2 mutations were found in the whole cohort either. The results showed
that CRLF2 overexpression and P2RY8-CRLF2 were associated with a poor outcome in 
unselected B-ALL. Moreover, in an intermediate risk B-ALL subgroup P2RY8-CRLF2
was correlated with worse survival, whereas in high- and low-risk subgroups,
CRLF2 overexpression predicted a poor outcome. Our findings suggest that
P2RY8-CRLF2 is an independent prognostic indicator in intermediate risk B-ALL,
while CRLF2 overexpression is correlated with an inferior outcome in high- or
low-risk B-ALL. Our study demonstrates that the impact of P2RY8-CRLF2 and CRLF2
overexpression on B-ALL survival may differ across risk subgroups. © 2016 Wiley
Periodicals, Inc.","© 2016 Wiley Periodicals, Inc.","DOI: 10.1002/gcc.22421 
PMID: 27637012  [Indexed for MEDLINE]"
"4. J Mol Diagn. 2016 Jul;18(4):595-603. doi: 10.1016/j.jmoldx.2016.03.004. Epub 2016
May 6.","Genome-Wide Single-Nucleotide Polymorphism Array Analysis Improves
Prognostication of Acute Lymphoblastic Leukemia/Lymphoma.","Wang Y(1), Miller S(2), Roulston D(2), Bixby D(3), Shao L(4).","Author information: 
(1)Clinical Cytogenetics Laboratory, University of Michigan, Ann Arbor, Michigan;
Department of Pathology, Peking University First Hospital, Beijing, China.
(2)Clinical Cytogenetics Laboratory, University of Michigan, Ann Arbor, Michigan.
(3)Department of Pathology, and the Department of Internal Medicine, University
of Michigan, Ann Arbor, Michigan.
(4)Clinical Cytogenetics Laboratory, University of Michigan, Ann Arbor, Michigan.
Electronic address: linashao@med.umich.edu.","Chromosomal abnormalities are important for the risk stratification of acute
lymphoblastic leukemia/lymphoma (ALL). However, approximately 30% of pediatric
and 50% of adult patients lack abnormalities with clinical relevance by
traditional cytogenetic analysis. We integrated cytogenetic, fluorescence in situ
hybridization, and whole-genome single-nucleotide polymorphism array results from
60 consecutive clinical ALL cases. By cytogenetic and/or fluorescence in situ
hybridization analyses, recurring abnormalities with clinical relevance were
observed in 33 B-cell ALL (B-ALL), including t(9;22), hyperdiploidy, KMT2A
translocation, ETV6-RUNX1, intrachromosomal amplification of chromosome 21, near 
haploidy or low hypodiploidy, and t(8;22). Single-nucleotide polymorphism array
analysis found additional aberrations with prognostic or therapeutic implication 
in 21 B-ALL and two T-cell ALL, including IKZF1 deletion, intrachromosomal
amplification of chromosome 21 (one case with a normal karyotype), low
hypodiploidy (two cases with a normal karyotype), and one case each with fusion
genes ETV6-NTRK3, CRLF2-P2RY8, NUP214-ABL1, and SET-NUP214. IKZF1 deletion was
noted in nine B-ALL with t(9;22), one B-ALL with t(4;11), five B-ALL with a
normal karyotype, and three B-ALL with nonrecurring karyotypic abnormalities.
Combining single-nucleotide polymorphism array with chromosome and fluorescence
in situ hybridization assays, the detection rate for clinically significant
abnormal results increased from 56% to 75%. Whole-genome single-nucleotide
polymorphism array analysis detects cytogenetically undetectable
clinically significant aberrations and should be routinely applied at diagnosis
of ALL.",Published by Elsevier Inc.,"DOI: 10.1016/j.jmoldx.2016.03.004 
PMID: 27161658  [Indexed for MEDLINE]"
"5. Leuk Res. 2016 Feb;41:36-42. doi: 10.1016/j.leukres.2015.11.018. Epub 2015 Dec
23.","CRLF2 overexpression identifies an unfavourable subgroup of adult B-cell
precursor acute lymphoblastic leukemia lacking recurrent genetic abnormalities.","Chiaretti S(1), Brugnoletti F(1), Messina M(1), Paoloni F(2), Fedullo AL(1),
Piciocchi A(2), Elia L(1), Vitale A(1), Mauro E(3), Ferrara F(4), De Fabritiis
P(5), Luppi M(6), Ronco F(7), De Propris MS(1), Raponi S(1), Kronnie GT(8),
Vignetti M(2), Guarini A(1), Foà R(9).","Author information: 
(1)Hematology, Department of Cellular Biotechnologies and Hematology, ""Sapienza"" 
University of Rome, Italy.
(2)GIMEMA Data Center, Rome, Italy.
(3)Division of Hematology, AOU Policlinico-OVE, University of Catania, Italy.
(4)Division of Hematology and Stem Cell Transplantation Unit, Cardarelli
Hospital, Naples, Italy.
(5)Hematology, Sant'Eugenio Hospital, Rome, Italy.
(6)Hematology Division, Department of Medical and Surgical Sciences, University
of Modena and Reggio Emilia, Modena, Italy.
(7)Hematology Unit, Azienda Ospedaliera Bianchi Melacrino Morelli, Reggio
Calabria, Italy.
(8)Laboratory of Oncohematology, Department of Women's and Children's Health,
University of Padova, Italy.
(9)Hematology, Department of Cellular Biotechnologies and Hematology, ""Sapienza"" 
University of Rome, Italy. Electronic address: rfoa@bce.uniroma1.it.","BACKGROUND: A deregulated CRLF2 (d-CRLF2) expression was described in B-cell
acute lymphoblastic leukemia without recurrent fusion genes (B-NEG ALL). While
the role of d-CRLF2 in children has been extensively described, little is known
about its role and impact in adult ALL.
METHODS: Expression levels of CRLF2 were evaluated by quantitative real-time PCR 
in 102 newly-diagnosed adult B-NEG ALL and correlated with the clinico-biological
characteristics and outcome. Incidence and clinical impact of the P2RY8/CRLF2
transcript was also assessed.
RESULTS: High CRLF2 levels, as continuous variable, were significantly associated
with hyperleucocytosis (p=0.0002) and thrombocytopenia (p=0.005); when a
cut-point at ΔCt≤8 was applied, 35 cases (34.3%), mostly males (80%), proved
positive for CRLF2 expression. High CRLF2 levels, as continuous or categorical
variable, were associated with a worse disease-free (p=0.003 and p=0.015) and
overall survival (p=0.017 and 0.0038). Furthermore, when CRLF2 was analyzed as a 
categorical variable, a high statistical association was found with IKZF1
deletion and mutations in the JAK/STAT pathway (p=0.001 and p<0.0001,
respectively). Finally, the P2RY8/CRLF2 transcript, identified in 8/102 patients 
(7.8%), was associated with a poor outcome.
CONCLUSIONS: In adult B-NEG ALL, high CRLF2 expression is associated with
distinct clinico-biological features and an unfavourable prognosis in both
univariate and multivariate analysis; similarly, P2RY8/CRLF2 positivity
correlates with a poor outcome. The quantification of CRLF2 is an important
prognostic marker in adult B-lineage ALL without known genetic lesions.",Copyright © 2015 Elsevier Ltd. All rights reserved.,"DOI: 10.1016/j.leukres.2015.11.018 
PMID: 26754556  [Indexed for MEDLINE]"
"6. J Exp Med. 2015 Dec 14;212(13):2213-22. doi: 10.1084/jem.20151250. Epub 2015 Nov 
16.","The G protein-coupled receptor P2RY8 and follicular dendritic cells promote
germinal center confinement of B cells, whereas S1PR3 can contribute to their
dissemination.","Muppidi JR(1), Lu E(2), Cyster JG(3).","Author information: 
(1)Department of Microbiology and Immunology, University of California, San
Francisco, San Francisco, CA 94143 Department of Medicine, University of
California, San Francisco, San Francisco, CA 94143 Howard Hughes Medical
Institute, University of California, San Francisco, San Francisco, CA 94143.
(2)Department of Microbiology and Immunology, University of California, San
Francisco, San Francisco, CA 94143 Howard Hughes Medical Institute, University of
California, San Francisco, San Francisco, CA 94143.
(3)Department of Microbiology and Immunology, University of California, San
Francisco, San Francisco, CA 94143 Howard Hughes Medical Institute, University of
California, San Francisco, San Francisco, CA 94143 Jason.Cyster@ucsf.edu.","The orphan Gα13-coupled receptor P2RY8 is mutated in human germinal center
(GC)-derived lymphomas and was recently found to promote B cell association with 
GCs in a mouse model. Here we establish that P2RY8 promotes clustering of
activated B cells within follicles in a follicular dendritic cell (FDC)-dependent
manner. Although mice lack a P2RY8 orthologue, we show that mouse GC B cell
clustering is also dependent on FDCs acting to support the function of a
Gα13-coupled receptor. Mutations in GNA13 and its downstream effector ARHGEF1 are
associated with the development of disseminated GC-derived lymphomas. We find
that egress of Gna13 mutant GC B cells from lymph nodes in the mouse depends on
sphingosine-1-phosphate receptor-3. These findings provide evidence that FDCs
promote GC confinement of both human and mouse GC B cells via Gα13-dependent
pathways, and they show that dissemination of Gα13-deficient GC B cells
additionally requires an egress-promoting receptor.",© 2015 Muppidi et al.,"DOI: 10.1084/jem.20151250 
PMCID: PMC4689170
PMID: 26573295  [Indexed for MEDLINE]"
7. Br J Haematol. 2015 Sep;170(6):847-58. doi: 10.1111/bjh.13514. Epub 2015 May 27.,"The clinical impact of IKZF1 deletions in paediatric B-cell precursor acute
lymphoblastic leukaemia is independent of minimal residual disease stratification
in Nordic Society for Paediatric Haematology and Oncology treatment protocols
used between 1992 and 2013.","Olsson L(1), Ivanov Öfverholm I(2), Norén-Nyström U(3), Zachariadis V(2),
Nordlund J(4), Sjögren H(5), Golovleva I(6), Nordgren A(2), Paulsson K(1), Heyman
M(7), Barbany G(2), Johansson B(1)(8).","Author information: 
(1)Division of Clinical Genetics, Department of Laboratory Medicine, Lund
University, Lund, Sweden.
(2)Department of Molecular Medicine and Surgery and Centre for Molecular
Medicine, Karolinska Institutet, Stockholm, Sweden.
(3)Department of Clinical Sciences, Paediatrics, Umeå University, Umeå, Sweden.
(4)Department of Medical Sciences, Molecular Medicine and Science for Life
Laboratory, Uppsala University, Uppsala, Sweden.
(5)Department of Clinical Chemistry and Transfusion Medicine, Institute of
Biomedicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg,
Sweden.
(6)Department of Medical Biosciences, Medical and Clinical Genetics, Umeå
University, Umeå, Sweden.
(7)Department of Women's and Children's Health, Karolinska Institutet, Stockholm,
Sweden.
(8)Department of Clinical Genetics, University and Regional Laboratories Region
Skåne, Lund, Sweden.","Paediatric B-cell precursor acute lymphoblastic leukaemias (BCP ALL) with IKZF1
deletions (∆IKZF1) are associated with a poor outcome. However, there are
conflicting data as to whether ∆IKZF1 is an independent risk factor if minimal
residual disease (MRD) and other copy number alterations also are taken into
account. We investigated 334 paediatric BCP ALL, diagnosed 1992-2013 and treated 
according to Nordic Society for Paediatric Haematology and Oncology ALL
protocols, with known IKZF1 status based on either single nucleotide polymorphism
array (N = 218) or multiplex ligation-dependent probe amplification (N = 116)
analyses. ∆IKZF1, found in 15%, was associated with inferior 10-year
probabilities of event-free (60% vs. 83%; P < 0·001) and overall survival (pOS;
73% vs. 89%; P = 0·001). Adjusting for known risk factors, including white blood 
cell (WBC) count and MRD, ∆IKZF1 was the strongest independent factor for relapse
and death. ∆IKZF1 was present in 27% of cases with non-informative cytogenetics
('BCP-other') and a poor 10-year pOS was particularly pronounced in this group
(58% vs. 90%; P < 0·001). Importantly, neither MRD nor WBC count predicted events
in the ∆IKZF1-positive cases. Co-occurrence of pseudoautosomal region 1 (PAR1)
deletions in Xp22.33/Yp11.32 (P2RY8-CRLF2) and ∆IKZF1 increased the risk of
relapse (75% vs. 30% for cases with only ∆IKZF1; P = 0·045), indicating that
BCP-other ALL with both P2RY8-CRLF2 and ∆IKZF1 constitutes a particularly
high-risk group.",© 2015 John Wiley & Sons Ltd.,"DOI: 10.1111/bjh.13514 
PMID: 26018335  [Indexed for MEDLINE]"
"8. PLoS One. 2015 Apr 16;10(4):e0124246. doi: 10.1371/journal.pone.0124246.
eCollection 2015.","Lymphocyte gene expression signatures from patients and mouse models of
hereditary hemochromatosis reveal a function of HFE as a negative regulator of
CD8+ T-lymphocyte activation and differentiation in vivo.","Costa M(1), Cruz E(2), Oliveira S(3), Benes V(4), Ivacevic T(4), Silva MJ(5),
Vieira I(3), Dias F(5), Fonseca S(5), Gonçalves M(5), Lima M(5), Leitão C(6),
Muckenthaler MU(7), Pinto J(3), Porto G(8).","Author information: 
(1)I3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto,
Porto, Portugal; Basic and Clinical Research on Iron Biology, IBMC-Instituto de
Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal; Doctoral
Program in Biomedicine, Faculdade de Medicina, Universidade do Porto, Porto,
Portugal.
(2)I3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto,
Porto, Portugal; Basic and Clinical Research on Iron Biology, IBMC-Instituto de
Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal; Clinical
Hematology, Santo António Hospital-Centro Hospitalar do Porto, Porto, Portugal.
(3)I3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto,
Porto, Portugal; Basic and Clinical Research on Iron Biology, IBMC-Instituto de
Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal.
(4)Genomics Core Facility, European Molecular Biology Laboratory, Heidelberg,
Germany.
(5)Clinical Hematology, Santo António Hospital-Centro Hospitalar do Porto, Porto,
Portugal.
(6)Advanced Flow Cytometry Unit, IBMC-Instituto de Biologia Molecular e Celular, 
Universidade do Porto, Porto, Portugal.
(7)Departments of Pediatric Hematology, Oncology and Immunology, University of
Heidelberg and Molecular Medicine Partnership Unit, Heidelberg, Germany.
(8)I3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto,
Porto, Portugal; Basic and Clinical Research on Iron Biology, IBMC-Instituto de
Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal; Clinical
Hematology, Santo António Hospital-Centro Hospitalar do Porto, Porto, Portugal;
Molecular Immunology and Pathology, ICBAS-Instituto de Ciências Biomédicas Abel
Salazar, Universidade do Porto, Porto, Portugal.","Abnormally low CD8+ T-lymphocyte numbers is characteristic of some patients with 
hereditary hemochromatosis (HH), a MHC-linked disorder of iron overload. Both
environmental and genetic components are known to influence CD8+ T-lymphocyte
homeostasis but the role of the HH associated protein HFE is still insufficiently
understood. Genome-wide expression profiling was performed in peripheral blood
CD8+ T lymphocytes from HH patients selected according to CD8+ T-lymphocyte
numbers and from Hfe-/- mice maintained either under normal or high iron diet
conditions. In addition, T-lymphocyte apoptosis and cell cycle progression were
analyzed by flow cytometry in HH patients. HH patients with low CD8+ T-lymphocyte
numbers show a differential expression of genes related to lymphocyte
differentiation and maturation namely CCR7, LEF1, ACTN1, NAA50, P2RY8 and FOSL2, 
whose expression correlates with the relative proportions of naïve, central and
effector memory subsets. In addition, expression levels of LEF1 and P2RY8 in
memory cells as well as the proportions of CD8+ T cells in G2/M cell cycle phase 
are significantly different in HH patients compared to controls. Hfe-/- mice do
not show alterations in CD8+ T-lymphocyte numbers but differential gene response 
patterns. We found an increased expression of S100a8 and S100a9 that is most
pronounced in high iron diet conditions. Similarly, CD8+ T lymphocytes from HH
patients display higher S100a9 expression both at the mRNA and protein level.
Altogether, our results support a role for HFE as a negative regulator of CD8+
T-lymphocyte activation. While the activation markers S100a8 and S100a9 are
strongly increased in CD8+ T cells from both, Hfe-/- mice and HH patients, a
differential profile of genes related to differentiation/maturation of CD8+ T
memory cells is evident in HH patients only. This supports the notion that HFE
contributes, at least in part, to the generation of low peripheral blood CD8+ T
lymphocytes in HH.","DOI: 10.1371/journal.pone.0124246 
PMCID: PMC4399836
PMID: 25880808  [Indexed for MEDLINE]"
9. Nature. 2014 Dec 11;516(7530):254-8. doi: 10.1038/nature13765. Epub 2014 Sep 28.,Loss of signalling via Gα13 in germinal centre B-cell-derived lymphoma.,"Muppidi JR(1), Schmitz R(2), Green JA(3), Xiao W(2), Larsen AB(4), Braun SE(5),
An J(5), Xu Y(5), Rosenwald A(6), Ott G(7), Gascoyne RD(8), Rimsza LM(9), Campo
E(10), Jaffe ES(11), Delabie J(12), Smeland EB(13), Braziel RM(14), Tubbs RR(15),
Cook JR(15), Weisenburger DD(16), Chan WC(17), Vaidehi N(4), Staudt LM(2), Cyster
JG(5).","Author information: 
(1)1] Department of Microbiology and Immunology, University of California, San
Francisco, California, 94143, USA [2] Department of Medicine, University of
California, San Francisco, California 94143, USA [3] Howard Hughes Medical
Institute, University of California, San Francisco, California 94143, USA.
(2)Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer
Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
(3)1] Department of Microbiology and Immunology, University of California, San
Francisco, California, 94143, USA [2] Howard Hughes Medical Institute, University
of California, San Francisco, California 94143, USA [3] Immunology Program,
Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
(4)Division of Immunology, Beckman Research Institute of the City of Hope,
Duarte, California 91010, USA.
(5)1] Department of Microbiology and Immunology, University of California, San
Francisco, California, 94143, USA [2] Howard Hughes Medical Institute, University
of California, San Francisco, California 94143, USA.
(6)Department of Pathology, University of Würzburg, 97080 Würzburg, Germany.
(7)1] Department of Clinical Pathology, Robert-Bosch-Krankenhaus, Auerbachstraße 
110, 70376 Stuttgart, Germany [2] Dr. Margarete Fischer-Bosch Institute for
Clinical Pharmacology, 70376 Stuttgart, Germany.
(8)British Columbia Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada.
(9)Department of Pathology, University of Arizona, Tucson, Arizona 85724, USA.
(10)Hospital Clinic, University of Barcelona, 08036 Barcelona, Spain.
(11)Laboratory of Pathology, Center for Cancer Research, National Cancer
Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
(12)Pathology Clinic, Rikshospitalet University Hospital, 0372 Oslo, Norway.
(13)1] Institute for Cancer Research, Rikshospitalet University Hospital,
University of Oslo, 0310 Oslo, Norway [2] Center for Cancer Biomedicine, Faculty 
Division of the Norwegian Radium Hospital, University of Oslo, 0310 Oslo, Norway.
(14)Oregon Health and Science University, Portland, Oregon 97239, USA.
(15)Cleveland Clinic Pathology and Laboratory Medicine Institute, Cleveland, Ohio
44195, USA.
(16)Department of Pathology, City of Hope National Medical Center, Duarte,
California 91010, USA.
(17)1] Department of Pathology, University of Nebraska Medical Center, Omaha,
Nebraska 68198, USA [2] Department of Microbiology, University of Nebraska
Medical Center, Omaha, Nebraska 68198, USA.","Germinal centre B-cell-like diffuse large B-cell lymphoma (GCB-DLBCL) is a common
malignancy, yet the signalling pathways that are deregulated and the factors
leading to its systemic dissemination are poorly defined. Work in mice showed
that sphingosine-1-phosphate receptor-2 (S1PR2), a Gα12 and Gα13 coupled
receptor, promotes growth regulation and local confinement of germinal centre B
cells. Recent deep sequencing studies of GCB-DLBCL have revealed mutations in
many genes in this cancer, including in GNA13 (encoding Gα13) and S1PR2 (refs
5,6, 7). Here we show, using in vitro and in vivo assays, that
GCB-DLBCL-associated mutations occurring in S1PR2 frequently disrupt the
receptor's Akt and migration inhibitory functions. Gα13-deficient mouse germinal 
centre B cells and human GCB-DLBCL cells were unable to suppress pAkt and
migration in response to S1P, and Gα13-deficient mice developed germinal centre
B-cell-derived lymphoma. Germinal centre B cells, unlike most lymphocytes, are
tightly confined in lymphoid organs and do not recirculate. Remarkably,
deficiency in Gα13, but not S1PR2, led to germinal centre B-cell dissemination
into lymph and blood. GCB-DLBCL cell lines frequently carried mutations in the
Gα13 effector ARHGEF1, and Arhgef1 deficiency also led to germinal centre B-cell 
dissemination. The incomplete phenocopy of Gα13- and S1PR2 deficiency led us to
discover that P2RY8, an orphan receptor that is mutated in GCB-DLBCL and another 
germinal centre B-cell-derived malignancy, Burkitt's lymphoma, also represses
germinal centre B-cell growth and promotes confinement via Gα13. These findings
identify a Gα13-dependent pathway that exerts dual actions in suppressing growth 
and blocking dissemination of germinal centre B cells that is frequently
disrupted in germinal centre B-cell-derived lymphoma.","DOI: 10.1038/nature13765 
PMCID: PMC4267955
PMID: 25274307  [Indexed for MEDLINE]"
10. Nat Commun. 2014 Aug 8;5:4654. doi: 10.1038/ncomms5654.,"Frequent cases of RAS-mutated Down syndrome acute lymphoblastic leukaemia lack
JAK2 mutations.","Nikolaev SI(1), Garieri M(2), Santoni F(3), Falconnet E(2), Ribaux P(2), Guipponi
M(4), Murray A(5), Groet J(5), Giarin E(6), Basso G(6), Nizetic D(7), Antonarakis
SE(8).","Author information: 
(1)1] Department of Genetic Medicine and Development, University of Geneva
Medical School, 1 rue Michel Servet, Geneva 1211, Switzerland [2].
(2)Department of Genetic Medicine and Development, University of Geneva Medical
School, 1 rue Michel Servet, Geneva 1211, Switzerland.
(3)1] Department of Genetic Medicine and Development, University of Geneva
Medical School, 1 rue Michel Servet, Geneva 1211, Switzerland [2] Geneva
University Hospitals-HUG, Service of Genetic Medicine, 4 Rue
Gabrielle-Perret-Gentil, Geneva 1211, Switzerland.
(4)Geneva University Hospitals-HUG, Service of Genetic Medicine, 4 Rue
Gabrielle-Perret-Gentil, Geneva 1211, Switzerland.
(5)1] The Blizard Institute, Barts and The London School of Medicine, Queen Mary 
University of London, 4 Newark Street, London E1 2AT, UK [2] LonDownS Consortium,
The Wellcome Trust, London NW1 2BE, UK.
(6)Dipartimento di Salute della Donna e del Bambino, University of Padua,
IRP-Istituto di Ricerca Pediatrica-Fondazione Città della Speranza, Via N.
Giustiniani 3, 35129 Padua, Italy.
(7)1] The Blizard Institute, Barts and The London School of Medicine, Queen Mary 
University of London, 4 Newark Street, London E1 2AT, UK [2] LonDownS Consortium,
The Wellcome Trust, London NW1 2BE, UK [3] Lee Kong Chian School of Medicine,
Nanyang Technological University, Unit 04-11, Proteos Building, 61 Biopolis
Drive, Singapore 138673, Singapore [4].
(8)1] Department of Genetic Medicine and Development, University of Geneva
Medical School, 1 rue Michel Servet, Geneva 1211, Switzerland [2] IGE3 institute 
of Genetics and Genomics of Geneva, 1 rue Michel Servet, Geneva 1211, Switzerland
[3].","Children with Down syndrome (DS) and acute lymphoblastic leukaemia (ALL) have
poorer survival and more relapses than non-DS children with ALL, highlighting an 
urgent need for deeper mechanistic understanding of DS-ALL. Here, using
full-exome or cancer genes-targeted sequencing of 42 ALL samples from 39 DS
patients, we uncover driver mutations in RAS, (KRAS and NRAS) recurring to a
similar extent (15/42) as JAK2 (12/42) mutations or P2RY8-CRLF2 fusions (14/42). 
RAS mutations are almost completely mutually exclusive with JAK2 mutations
(P=0.016), driving a combined total of two-thirds of analysed cases. Clonal
architecture analysis reveals that both RAS and JAK2 drove sub-clonal expansions 
primarily initiated by CRLF2 rearrangements, and/or mutations in chromatin
remodellers and lymphocyte differentiation factors. Remarkably, in 2/3 relapsed
cases, there is a switch from a primary JAK2- or PTPN11-mutated sub-clone to a
RAS-mutated sub-clone in relapse. These results provide important new insights
informing the patient stratification strategies for targeted therapeutic
approaches for DS-ALL.","DOI: 10.1038/ncomms5654 
PMCID: PMC4665216
PMID: 25105841  [Indexed for MEDLINE]"
"11. Genes Chromosomes Cancer. 2014 Nov;53(11):902-10. doi: 10.1002/gcc.22201. Epub
2014 Jul 16.","Gene alterations involving the CRLF2-JAK pathway and recurrent gene deletions in 
Down syndrome-associated acute lymphoblastic leukemia in Japan.","Hanada I(1), Terui K, Ikeda F, Toki T, Kanezaki R, Sato T, Kamio T, Kudo K,
Sasaki S, Takahashi Y, Hayashi Y, Inukai T, Kojima S, Koike K, Kosaka Y,
Kobayashi M, Imaizumi M, Mitsui T, Hori H, Hara J, Horibe K, Nagai J, Goto H, Ito
E.","Author information: 
(1)Department of Pediatrics, Hirosaki University Graduate School of Medicine,
Hirosaki, Japan.","In Western countries, gene alterations involving the CRLF2-JAK signaling pathway 
are identified in approximately 50-60% of patients with Down syndrome-associated 
acute lymphoblastic leukemia (DS-ALL), and this pathway is considered a potential
therapeutic target. The frequency of BTG1 deletions in DS-ALL is controversial.
IKZF1 deletions, found in 20-30% of DS-ALL patients, are associated with a poor
outcome and EBF1 deletions are very rare (∼2%). We analyzed 38 patients to
determine the frequencies and clinical implications of CRLF2-JAK pathway genetic 
alterations and recurrent gene deletions in Japanese DS-ALL patients. We
confirmed a high incidence of P2RY8-CRLF2 (29%) and JAK2 mutations (16%), though 
the frequency of P2RY8-CRLF2 was slightly lower than that in Western countries
(∼50%). BTG1 deletions were common in our cohort (25%). IKZF1 deletions were
detected in 25% of patients and associated with shorter overall survival (OS).
EBF1 deletions were found at an unexpectedly high frequency (16%), and at a
significantly higher level in P2RY8-CRLF2-positive patients than in
P2RY8-CRLF2-negative patients (44% vs. 4%, P=0.015). Deletions of CDKN2A/B and
PAX5 were common in P2RY8-CRLF2-negative patients (48 and 39%, respectively) but 
not in P2RY8-CRLF2-positive patients (11% each). Associations between these
genetic alterations and clinical characteristics were not observed except for
inferior OS in patients with IKZF1 deletions. These results suggest that
differences exist between the genetic profiles of DS-ALL patients in Japan and in
Western countries, and that P2RY8-CRLF2 and EBF1 deletions may cooperate in
leukemogenesis in a subset of Japanese DS-ALL patients.","© 2014 Wiley Periodicals, Inc.","DOI: 10.1002/gcc.22201 
PMID: 25044358  [Indexed for MEDLINE]"
"12. Genes Chromosomes Cancer. 2014 Oct;53(10):815-23. doi: 10.1002/gcc.22190. Epub
2014 Jun 17.","An overall characterization of pediatric acute lymphoblastic leukemia with CRLF2 
overexpression.","Yano M(1), Imamura T, Asai D, Moriya-Saito A, Suenobu S, Hasegawa D, Deguchi T,
Hashii Y, Kawasaki H, Hori H, Kosaka Y, Kato K, Horibe K, Yumura-Yagi K, Hara J, 
Matsumoto K, Kiyokawa N, Oda M, Sato A; Japan Association of Childhood Leukemia
Study.","Author information: 
(1)Department of Pediatrics, Kyoto Prefectural University of Medicine, Graduate
School of Medical Science, Kyoto, Japan.","For an overall characterization of pediatric B-cell precursor acute lymphoblastic
leukemia (BCPALL) with CRLF2 overexpression (OE), we conducted genetic analysis
of CRLF2 in 167 pediatric BCPALL patients. CRLF2 OE was detected in 30 (18%) of
167 patients, the P2RY8-CRLF2 fusion was identified in only 3 (1.8%) of 167
patients, all of which demonstrated CRLF2 OE. Moreover, CRLF2 gain was identified
in 18 (11%) of 167 patients. Messenger RNA sequencing revealed a novel fusion
transcript, CSF2RA-CRLF2, in a case with CRLF2 OE, suggesting that this fusion is
associated with CRLF2 OE. In survival analysis, no significant differences in
5-year event-free survival (EFS) and overall survival were observed between
patients with and without CRLF2 OE (70.7 vs. 75.4%, log rank P = 0.68 and 96.4
vs. 82.1%, log rank P = 0.11, respectively). However, a significant difference in
5-year EFS between CRLF2 OE patients with and without IKZF1 deletion was observed
(44.4 vs. 83.1%, log rank P = 0.02). In multivariate analysis, only IKZF1
deletion was a significant predictor of inferior OS (hazard ratio: 2.427, P =
0.04).These findings suggest that CRLF2 OE is not an independent prognostic
factor in pediatric BCPALL.","© 2014 Wiley Periodicals, Inc.","DOI: 10.1002/gcc.22190 
PMID: 24935070  [Indexed for MEDLINE]"
"13. Immunobiology. 2013 Nov;218(11):1345-53. doi: 10.1016/j.imbio.2013.07.001. Epub
2013 Jul 15.","An mRNA atlas of G protein-coupled receptor expression during primary human
monocyte/macrophage differentiation and lipopolysaccharide-mediated activation
identifies targetable candidate regulators of inflammation.","Hohenhaus DM(1), Schaale K, Le Cao KA, Seow V, Iyer A, Fairlie DP, Sweet MJ.","Author information: 
(1)Institute for Molecular Bioscience, The University of Queensland, Brisbane,
Qld 4072, Australia; Australian Infectious Disease Research Centre, The
University of Queensland, Brisbane, Qld 4072, Australia.","G protein-coupled receptors (GPCRs) are among the most important targets in drug 
discovery. In this study, we used TaqMan Low Density Arrays to profile the full
GPCR repertoire of primary human macrophages differentiated from monocytes using 
either colony stimulating factor-1 (CSF-1/M-CSF) (CSF-1 Mϕ) or granulocyte
macrophage colony stimulating factor (GM-CSF) (GM-CSF Mϕ). The overall trend was 
a downregulation of GPCRs during monocyte to macrophage differentiation, but a
core set of 10 genes (e.g. LGR4, MRGPRF and GPR143) encoding seven transmembrane 
proteins were upregulated, irrespective of the differentiating agent used.
Several of these upregulated GPCRs have not previously been studied in the
context of macrophage biology and/or inflammation. As expected, CSF-1 Mϕ and
GM-CSF Mϕ exhibited differential inflammatory cytokine profiles in response to
the Toll-like Receptor (TLR)4 agonist lipopolysaccharide (LPS). Moreover, 15
GPCRs were differentially expressed between these cell populations in the basal
state. For example, EDG1 was expressed at elevated levels in CSF-1 Mϕ versus
GM-CSF Mϕ, whereas the reverse was true for EDG6. 101 GPCRs showed differential
regulation over an LPS time course, with 65 of these profiles being impacted by
the basal differentiation state (e.g. GPRC5A, GPRC5B). Only 14 LPS-regulated
GPCRs showed asynchronous behavior (divergent LPS regulation) with respect to
differentiation status. Thus, the differentiation state primarily affects the
magnitude of LPS-regulated expression, rather than causing major reprogramming of
GPCR gene expression profiles. Several GPCRs showing differential profiles
between CSF-1 Mϕ and GM-CSF Mϕ (e.g. P2RY8, GPR92, EMR3) have not been widely
investigated in macrophage biology and inflammation. Strikingly, several closely 
related GPCRs displayed completely opposing patterns of regulation during
differentiation and/or activation (e.g. EDG1 versus EDG6, LGR4 versus LGR7,
GPRC5A versus GPRC5B). We propose that selective regulation of GPCR5A and GPCR5B 
in CSF-1 Mϕ contributes to skewing toward the M2 macrophage phenotype. Our
analysis of the GPCR repertoire expressed during primary human monocyte to
macrophage differentiation and TLR4-mediated activation provides a valuable new
platform for conducting future functional analyses of individual GPCRs in human
macrophage inflammatory pathways.",Copyright © 2013 Elsevier GmbH. All rights reserved.,"DOI: 10.1016/j.imbio.2013.07.001 
PMID: 23948647  [Indexed for MEDLINE]"
14. Cancer Med. 2013 Jun;2(3):412-9. doi: 10.1002/cam4.87. Epub 2013 May 9.,"IKZF1 deletion is associated with a poor outcome in pediatric B-cell precursor
acute lymphoblastic leukemia in Japan.","Asai D(1), Imamura T, Suenobu S, Saito A, Hasegawa D, Deguchi T, Hashii Y,
Matsumoto K, Kawasaki H, Hori H, Iguchi A, Kosaka Y, Kato K, Horibe K,
Yumura-Yagi K, Hara J, Oda M; Japan Association of Childhood Leukemia Study
(JACLS).","Author information: 
(1)Department of Pediatrics, Kyoto Prefectural University of Medicine, Graduate
School of Medical Science, Kyoto, Japan.","Genetic alterations of Ikaros family zinc finger protein 1 (IKZF1), point
mutations in Janus kinase 2 (JAK2), and overexpression of cytokine receptor-like 
factor 2 (CRLF2) were recently reported to be associated with poor outcomes in
pediatric B-cell precursor (BCP)-ALL. Herein, we conducted genetic analyses of
IKZF1 deletion, point mutation of JAK2 exon 16, 17, and 21, CRLF2 expression, the
presence of P2RY8-CRLF2 fusion and F232C mutation in CRLF2 in 202 pediatric
BCP-ALL patients newly diagnosed and registered in Japan Childhood Leukemia Study
ALL02 protocol to find out if alterations in these genes are determinants of poor
outcome. All patients showed good response to initial prednisolone (PSL)
treatment. Ph⁺, infantile, and Down syndrome-associated ALL were excluded.
Deletion of IKZF1 occurred in 19/202 patients (9.4%) and CRLF2 overexpression
occurred in 16/107 (15.0%), which are similar to previous reports. Patients with 
IKZF1 deletion had reduced event-free survival (EFS) and overall survival (OS)
compared to those in patients without IKZF1 deletion (5-year EFS, 62.7% vs.
88.8%, 5-year OS, 71.8% vs. 90.2%). Our data also showed significantly inferior
5-year EFS (48.6% vs. 84.7%, log rank P = 0.0003) and 5-year OS (62.3% vs. 85.4%,
log rank P = 0.009) in NCI-HR patients (n = 97). JAK2 mutations and P2RY8-CRLF2
fusion were rarely detected. IKZF1 deletion was identified as adverse prognostic 
factor even in pediatric BCP-ALL in NCI-HR showing good response to PSL.","DOI: 10.1002/cam4.87 
PMCID: PMC3699852
PMID: 23930217  [Indexed for MEDLINE]"
"15. Haematologica. 2014 Jan;99(1):103-10. doi: 10.3324/haematol.2013.090225. Epub
2013 Aug 2.","High CD45 surface expression determines relapse risk in children with precursor
B-cell and T-cell acute lymphoblastic leukemia treated according to the ALL-BFM
2000 protocol.","Cario G(1), Rhein P, Mitlöhner R, Zimmermann M, Bandapalli OR, Romey R, Moericke 
A, Ludwig WD, Ratei R, Muckenthaler MU, Kulozik AE, Schrappe M, Stanulla M,
Karawajew L.","Author information: 
(1)g.cario@pediatrics.uni-kiel.de.","Further improvement of outcome in childhood acute lymphoblastic leukemia could be
achieved by identifying additional high-risk patients who may benefit from
intensified treatment. We earlier identified PTPRC (CD45) gene expression as a
potential new stratification marker and now analyzed the prognostic relevance of 
CD45 protein expression. CD45 was measured by flow cytometry in 1065 patients
treated according to the ALL-BFM-2000 protocol. The 75(th) percentile was used as
cut-off to distinguish a CD45-high from a CD45-low group. As mean CD45 expression
was significantly higher in T-cell acute lymphoblastic leukemia than in
B-cell-precursor acute lymphoblastic leukemia (P<0.0001), the analysis was
performed separately in both groups. In B-cell-precursor acute lymphoblastic
leukemia we observed a significant association of a high CD45 expression with
older age, high initial white blood cell count, ETV6/RUNX1 negativity, absence of
high hyperdiploidy (P<0.0001), MLL/AF4 positivity (P=0.002), BCR/ABL1 positivity 
(P=0.007), prednisone poor response (P=0.002) and minimal residual disease
(P<0.0001). In T-cell acute lymphoblastic leukemia we observed a significant
association with initial white blood cell count (P=0.0003), prednisone poor
response (P=0.01), and minimal residual disease (P=0.02). Compared to CD45-low
patients, CD45-high patients had a lower event-free survival rate
(B-cell-precursor acute lymphoblastic leukemia: 72 ± 3% versus 86 ± 1%, P<0.0001;
T-cell acute lymphoblastic leukemia: 60 ± 8% versus 78 ± 4%, P=0.02), which was
mainly attributable to a higher cumulative relapse incidence (B-cell-precursor
acute lymphoblastic leukemia: 22 ± 3% versus 11 ± 1%, P<0.0001; T-cell acute
lymphoblastic leukemia: 31 ± 8% versus 11 ± 3%, P=0.003) and kept its
significance in multivariate analysis considering sex, age, initial white blood
cell count, and minimal residual disease in B-cell-precursor- and T-cell acute
lymphoblastic leukemia, and additionally presence of ETV6/RUNX1, MLL/AF4 and
BCR/ABL1 rearrangements in B-cell-precursor acute lymphoblastic leukemia (P=0.002
and P=0.025, respectively). Consideration of CD45 expression may serve as an
additional stratification tool in BFM-based protocols. (ClinicalTrials.gov
identifier: NCT00430118).","DOI: 10.3324/haematol.2013.090225 
PMCID: PMC4007934
PMID: 23911702  [Indexed for MEDLINE]"
"16. Blood. 2013 Jan 17;121(3):485-8. doi: 10.1182/blood-2012-04-422691. Epub 2012 Dec
4.","Tyrosine kinome sequencing of pediatric acute lymphoblastic leukemia: a report
from the Children's Oncology Group TARGET Project.","Loh ML(1), Zhang J, Harvey RC, Roberts K, Payne-Turner D, Kang H, Wu G, Chen X,
Becksfort J, Edmonson M, Buetow KH, Carroll WL, Chen IM, Wood B, Borowitz MJ,
Devidas M, Gerhard DS, Bowman P, Larsen E, Winick N, Raetz E, Smith M, Downing
JR, Willman CL, Mullighan CG, Hunger SP.","Author information: 
(1)Department of Pediatrics and the Helen Diller Family Cancer Center, University
of California-San Francisco, CA, USA.","One recently identified subtype of pediatric B-precursor acute lymphoblastic
leukemia (ALL) has been termed BCR-ABL1-like or Ph-like because of similarity of 
the gene expression profile to BCR-ABL1 positive ALL suggesting the presence of
lesions activating tyrosine kinases, frequent alteration of IKZF1, and poor
outcome. Prior studies demonstrated that approximately half of these patients had
genomic lesions leading to CRLF2 overexpression, with half of such cases
harboring somatic mutations in the Janus kinases JAK1 and JAK2. To determine
whether mutations in other tyrosine kinases might also occur in ALL, we sequenced
the tyrosine kinome and downstream signaling genes in 45 high-risk pediatric ALL 
cases with either a Ph-like gene expression profile or other alterations
suggestive of activated kinase signaling. Aside from JAK mutations and 1 FLT3
mutation, no somatic mutations were found in any other tyrosine kinases,
suggesting that alternative mechanisms are responsible for activated kinase
signaling in high-risk ALL.","DOI: 10.1182/blood-2012-04-422691 
PMCID: PMC3548168
PMID: 23212523  [Indexed for MEDLINE]"
"18. Blood. 2012 Dec 20;120(26):5134-42. doi: 10.1182/blood-2012-07-443218. Epub 2012 
Oct 22.","Small sizes and indolent evolutionary dynamics challenge the potential role of
P2RY8-CRLF2-harboring clones as main relapse-driving force in childhood ALL.","Morak M(1), Attarbaschi A, Fischer S, Nassimbeni C, Grausenburger R, Bastelberger
S, Krentz S, Cario G, Kasper D, Schmitt K, Russell LJ, Pötschger U, Stanulla M,
Eckert C, Mann G, Haas OA, Panzer-Grümayer R.","Author information: 
(1)Children's Cancer Research Institute, St Anna Kinderkrebsforschung, Vienna,
Austria.","Erratum in
    Blood. 2013 Aug 15;122(7):1328.","The P2RY8-CRLF2 fusion defines a particular relapse-prone subset of childhood
acute lymphoblastic leukemia (ALL) in Italian Association of Pediatric Hematology
and Oncology Berlin-Frankfurt-Münster (AIEOP-BFM) 2000 protocols. To investigate 
whether and to what extent different clone sizes influence disease and relapse
development, we quantified the genomic P2RY8-CRLF2 fusion product and correlated 
it with the corresponding CRLF2 expression levels in patients enrolled in the
BFM-ALL 2000 protocol in Austria. Of 268 cases without recurrent chromosomal
translocations and high hyperdiploidy, representing approximately 50% of all
cases, 67 (25%) were P2RY8-CRLF2 positive. The respective clone sizes were ≥ 20% 
in 27% and < 20% in 73% of them. The cumulative incidence of relapse of the
entire fusion-positive group was clone size independent and significantly higher 
than that of the fusion-negative group (35% ± 8% vs 13% ± 3%, P = .008) and
primarily confined to the non-high-risk group. Of 22 P2RY8-CRLF2-positive
diagnosis/relapse pairs, only 4/8 had the fusion-positive dominant clone
conserved at relapse, whereas none of the original 14 fusion-positive small
clones reappeared as the dominant relapse clone. We conclude that the majority of
P2RY8-CRLF2-positive clones are small at diagnosis and virtually never generate a
dominant relapse clone. Our findings therefore suggest that P2RY8-CRLF2-positive 
clones do not have the necessary proliferative or selective advantage to evolve
into a disease-relevant relapse clone.","DOI: 10.1182/blood-2012-07-443218 
PMCID: PMC4194314
PMID: 23091296  [Indexed for MEDLINE]"
"19. Haematologica. 2013 Mar;98(3):428-32. doi: 10.3324/haematol.2011.056135. Epub
2012 Aug 8.","IKZF1 deletion is an independent predictor of outcome in pediatric acute
lymphoblastic leukemia treated according to the ALL-BFM 2000 protocol.","Dörge P(1), Meissner B, Zimmermann M, Möricke A, Schrauder A, Bouquin JP, Schewe 
D, Harbott J, Teigler-Schlegel A, Ratei R, Ludwig WD, Koehler R, Bartram CR,
Schrappe M, Stanulla M, Cario G.","Author information: 
(1)Department of Pediatrics, University Medical Centre Schleswig-Holstein, Kiel, 
Germany.","IKZF1 gene deletions have been associated with a poor outcome in pediatric
precursor B-cell acute lymphoblastic leukemia. To assess the prognostic relevance
of IKZF1 deletions for patients treated on Berlin-Frankfurt-Münster Study Group
trial ALL-BFM 2000, we screened 694 diagnostic acute lymphoblastic leukemia
samples by Multiplex Ligation-dependent Probe Amplification. Patients whose
leukemic cells bore IKZF1 deletions had a lower 5-year event-free survival
(0.69±0.05 vs. 0.85±0.01; P<0.0001) compared to those without, mainly due to a
higher cumulative incidence of relapses (0.21±0.04 vs. 0.10±0.01; P=0.001).
Although IKZF1 deletions were significantly associated with the P2RY8-CRLF2
rearrangement, their prognostic value was found to be independent from this
association. Thus, IKZF1 deletion is an independent predictor of treatment
outcome and a strong candidate marker for integration in future treatment
stratification strategies on ALL-BFM protocols. Clinicaltrials.gov identifier:
NCT00430118.","DOI: 10.3324/haematol.2011.056135 
PMCID: PMC3659952
PMID: 22875627  [Indexed for MEDLINE]"
"20. J Clin Oncol. 2012 Sep 1;30(25):3100-8. doi: 10.1200/JCO.2011.40.3907. Epub 2012 
Jul 30.","IGH@ translocations, CRLF2 deregulation, and microdeletions in adolescents and
adults with acute lymphoblastic leukemia.","Moorman AV(1), Schwab C, Ensor HM, Russell LJ, Morrison H, Jones L, Masic D,
Patel B, Rowe JM, Tallman M, Goldstone AH, Fielding AK, Harrison CJ.","Author information: 
(1)Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research,
Level 5, Sir James Spence Institute, Royal Victoria Infirmary, Queen Victoria Rd,
Newcastle-upon-Tyne, NE1 4LP, United Kingdom. anthony.moorman@ncl.ac.uk","PURPOSE: To determine the prevalence and prognostic impact of significant acute
lymphoblastic leukemia (ALL) -related genes: CRLF2 deregulation (CRLF2-d), IGH@
translocations (IGH@-t), and deletions of CDKN2A/B, IKZF1, PAX5, ETV6, RB1, BTG1,
and EBF1 in adolescents and adults.
PATIENTS AND METHODS: The cohort comprised 454 patients (age 15 to 60 years old) 
treated on the multicenter United Kingdom Acute Lymphoblastic Leukaemia Trial
XII/Eastern Cooperative Oncology Group 2993 trial (UKALLXII/ECOG2993) with
Philadelphia-negative B-cell precursor ALL. Fluorescent in situ hybridization and
multiplex ligation-dependent probe amplification were used to detect these
genetic alterations.
RESULTS: Twenty patients (5%) had CRLF2-d (P2RY8-CRLF2, n = 7; IGH@-CRLF2, n =
13), and 36 patients (8%) harbored an IGH@-t with a different partner gene. There
was little overlap between IGH@-t, CRLF2-d, and established chromosomal
abnormalities. Deletions of CDKN2A/B, IKZF1, PAX5, ETV6, RB1, BTG1, or EBF1 were 
prevalent with 101 (33%) of 304 patients harboring one and 102 (33%) harboring
two or more alterations, occurring with varying frequency in all cytogenetic
subgroups. The 5-year event-free survival, relapse-free survival (RFS), and
overall survival (OS) rates for the whole cohort were 40%, 55%, and 43%,
respectively. Patients with CRLF2-d, IGH@-t, and IKZF1 deletions were associated 
with an inferior outcome in univariate but not multivariate analysis. In
particular, CRLF2-d patients had a lower RFS compared with other patients (30%), 
whereas those with IGH@-t or IKZF1 deletions had a lower OS (27% and 35%,
respectively).
CONCLUSION: CRLF2-d and IGH@-t represent distinct subtypes of adolescent and
adult ALL. Deletions of key B-cell differentiation and cell cycle control genes
are highly prevalent but vary in frequency by cytogenetic subgroup. CRLF2-d,
IGH@-t, and IKZF1 deletions are associated with poor outcome in adolescent and
adult ALL.","DOI: 10.1200/JCO.2011.40.3907 
PMID: 22851563  [Indexed for MEDLINE]",
"
1. Br J Haematol. 2012 Sep;158(6):772-7. doi: 10.1111/j.1365-2141.2012.09221.x. Epub
2012 Jul 23.","Treatment outcome of CRLF2-rearranged childhood acute lymphoblastic leukaemia: a 
comparative analysis of the AIEOP-BFM and UK NCRI-CCLG study groups.","Attarbaschi A(1), Morak M, Cario G, Cazzaniga G, Ensor HM, te Kronnie T, Bradtke 
J, Mann G, Vendramini E, Palmi C, Schwab C, Russell LJ, Schrappe M, Conter V,
Mitchell CD, Strehl S, Zimmermann M, Pötschger U, Harrison CJ, Stanulla M,
Panzer-Grümayer R, Haas OA, Moorman AV; Associazione Italiana di Ematologia ed
Oncologia Pediatrica (AIEOP)-Berlin-Frankfurt-Münster (BFM) Study Group and
National Cancer Research Institute (NCRI)-Children's Cancer and Leukaemia (CCLG) 
Study Group.","Author information: 
(1)Paediatric Haematology and Oncology, Department of Paediatrics, St. Anna
Children's Hospital, Medical University of Vienna, Vienna, Austria.
andishe.attarbaschi@stanna.at","The prognostic relevance of CRLF2 -rearrangements in childhood acute B-cell
precursor lymphoblastic leukaemia (ALL), was assessed by a comparative analysis
of 114 non-Down-syndrome patients (99 P2RY8-CRLF2+ , 15 IGH@-CRLF2+ ), 76 from
the AIEOP-BFM ALL 2000 and 38 from the MRC ALL97 trials. The 6-year cumulative
relapse incidence of P2RY8-CRLF2+ patients treated on the two trials was not
statistically different: 0·37 ± 0·06 vs. 0·25 ± 0·08 (P = 0·194). In contrast,
0/9 IGH@-CRLF2+ AIEOP-BFM, but 5/6 ALL97 patients relapsed. Conclusively,
P2RY8-CRLF2+ patients had an intermediate protocol-independent outcome while the 
different prognosis of IGH@-CRLF2+ patients could be related to the different
structures of the applied treatment protocols.",© 2012 Blackwell Publishing Ltd.,"DOI: 10.1111/j.1365-2141.2012.09221.x 
PMID: 22816614  [Indexed for MEDLINE]"
2. Leukemia. 2012 Oct;26(10):2245-53. doi: 10.1038/leu.2012.101. Epub 2012 Apr 9.,"Poor prognosis for P2RY8-CRLF2 fusion but not for CRLF2 over-expression in
children with intermediate risk B-cell precursor acute lymphoblastic leukemia.","Palmi C(1), Vendramini E, Silvestri D, Longinotti G, Frison D, Cario G, Shochat
C, Stanulla M, Rossi V, Di Meglio AM, Villa T, Giarin E, Fazio G, Leszl A,
Schrappe M, Basso G, Biondi A, Izraeli S, Conter V, Valsecchi MG, Cazzaniga G, Te
Kronnie G.","Author information: 
(1)Centro Ricerca Tettamanti, Clinica Pediatrica, Università di Milano Bicocca,
Ospedale San Gerardo, Monza, Italy.","Pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) has achieved an
80% cure rate as a result of a risk-adapted therapy largely based on minimal
residual disease (MRD) monitoring. However, relapse is still the most frequent
adverse event, occurring mainly in the patients with intermediate MRD levels
(intermediate risk, IR), emphasizing the need for new prognostic markers. We
analyzed the prognostic impact of cytokine receptor-like factor 2 (CRLF2)
over-expression and P2RY8-CRLF2 fusion in 464 BCP-ALL patients (not affected by
Down syndrome and BCR-ABL negative) enrolled in the AIEOP-BFM ALL2000 study in
Italy. In 22/464 (4.7%) samples, RQ-PCR showed CRLF2 over-expression (≥20 times
higher than the overall median). P2RY8-CRLF2 fusion was detected in 22/365 (6%)
cases, with 10/22 cases also showing CRLF2 over-expression. P2RY8-CRLF2 fusion
was the most relevant prognostic factor independent of CRLF2 over-expression with
a threefold increase in risk of relapse. Significantly, the cumulative incidence 
of relapse of the P2RY8-CRLF2 + patients in the IR group was high (61.1% ± 12.9
vs 17.6% ± 2.6, P<0.0001), similar to high-risk patients in AIEOP-BFM ALL2000
study. These results were confirmed in a cohort of patients treated in Germany.
In conclusion, P2RY8-CRLF2 identifies a subset of BCP-ALL patients currently
stratified as IR that could be considered for treatment intensification.","DOI: 10.1038/leu.2012.101 
PMID: 22484421  [Indexed for MEDLINE]"
"3. Blood. 2012 Apr 12;119(15):3512-22. doi: 10.1182/blood-2011-11-394221. Epub 2012 
Feb 24.","Outcome modeling with CRLF2, IKZF1, JAK, and minimal residual disease in
pediatric acute lymphoblastic leukemia: a Children's Oncology Group study.","Chen IM(1), Harvey RC, Mullighan CG, Gastier-Foster J, Wharton W, Kang H,
Borowitz MJ, Camitta BM, Carroll AJ, Devidas M, Pullen DJ, Payne-Turner D, Tasian
SK, Reshmi S, Cottrell CE, Reaman GH, Bowman WP, Carroll WL, Loh ML, Winick NJ,
Hunger SP, Willman CL.","Author information: 
(1)Cancer Center and Department of Internal Medicine, University of New Mexico,
Albuquerque, NM 87131-001, USA.","As controversy exists regarding the prognostic significance of genomic
rearrangements of CRLF2 in pediatric B-precursor acute lymphoblastic leukemia
(ALL) classified as standard/intermediate-risk (SR) or high-risk (HR), we
assessed the prognostic significance of CRLF2 mRNA expression, CRLF2 genomic
lesions (IGH@-CRLF2, P2RY8-CRLF2, CRLF2 F232C), deletion/mutation in genes
frequently associated with high CRLF2 expression (IKZF1, JAK, IL7R), and minimal 
residual disease (MRD) in 1061 pediatric ALL patients (499 HR and 562 SR) on COG 
Trials P9905/P9906. Whereas very high CRLF2 expression was found in 17.5% of
cases, only 51.4% of high CRLF2 expressors had CRLF2 genomic lesions. The
mechanism underlying elevated CRLF2 expression in cases lacking known genomic
lesions remains to be determined. All CRLF2 genomic lesions and virtually all JAK
mutations were found in high CRLF2 expressors, whereas IKZF1 deletions/mutations 
were distributed across the full cohort. In multivariate analyses, NCI risk
group, MRD, high CRLF2 expression, and IKZF1 lesions were associated with
relapse-free survival. Within HR ALL, only MRD and CRLF2 expression predicted a
poorer relapse-free survival; no difference was seen between cases with or
without CRLF2 genomic lesions. Thus, high CRLF2 expression is associated with a
very poor outcome in high-risk, but not standard-risk, ALL. This study is
registered at www.clinicaltrials.gov as NCT00005596 and NCT00005603.","DOI: 10.1182/blood-2011-11-394221 
PMCID: PMC3325039
PMID: 22368272  [Indexed for MEDLINE]"
"4. Proc Natl Acad Sci U S A. 2012 Mar 6;109(10):3879-84. doi:
10.1073/pnas.1121343109. Epub 2012 Feb 17.","Discovery and prioritization of somatic mutations in diffuse large B-cell
lymphoma (DLBCL) by whole-exome sequencing.","Lohr JG(1), Stojanov P, Lawrence MS, Auclair D, Chapuy B, Sougnez C,
Cruz-Gordillo P, Knoechel B, Asmann YW, Slager SL, Novak AJ, Dogan A, Ansell SM, 
Link BK, Zou L, Gould J, Saksena G, Stransky N, Rangel-Escareño C,
Fernandez-Lopez JC, Hidalgo-Miranda A, Melendez-Zajgla J, Hernández-Lemus E,
Schwarz-Cruz y Celis A, Imaz-Rosshandler I, Ojesina AI, Jung J, Pedamallu CS,
Lander ES, Habermann TM, Cerhan JR, Shipp MA, Getz G, Golub TR.","Author information: 
(1)Eli and Edythe Broad Institute, Cambridge, MA 02412, USA.","To gain insight into the genomic basis of diffuse large B-cell lymphoma (DLBCL), 
we performed massively parallel whole-exome sequencing of 55 primary tumor
samples from patients with DLBCL and matched normal tissue. We identified
recurrent mutations in genes that are well known to be functionally relevant in
DLBCL, including MYD88, CARD11, EZH2, and CREBBP. We also identified somatic
mutations in genes for which a functional role in DLBCL has not been previously
suspected. These genes include MEF2B, MLL2, BTG1, GNA13, ACTB, P2RY8, PCLO, and
TNFRSF14. Further, we show that BCL2 mutations commonly occur in patients with
BCL2/IgH rearrangements as a result of somatic hypermutation normally occurring
at the IgH locus. The BCL2 point mutations are primarily synonymous, and likely
caused by activation-induced cytidine deaminase-mediated somatic hypermutation,
as shown by comprehensive analysis of enrichment of mutations in WRCY target
motifs. Those nonsynonymous mutations that are observed tend to be found outside 
of the functionally important BH domains of the protein, suggesting that strong
negative selection against BCL2 loss-of-function mutations is at play. Last, by
using an algorithm designed to identify likely functionally relevant but
infrequent mutations, we identify KRAS, BRAF, and NOTCH1 as likely drivers of
DLBCL pathogenesis in some patients. Our data provide an unbiased view of the
landscape of mutations in DLBCL, and this in turn may point toward new
therapeutic strategies for the disease.","DOI: 10.1073/pnas.1121343109 
PMCID: PMC3309757
PMID: 22343534  [Indexed for MEDLINE]"
"5. Genes Chromosomes Cancer. 2012 Feb;51(2):196-206. doi: 10.1002/gcc.20944. Epub
2011 Nov 10.","High frequency of BTG1 deletions in acute lymphoblastic leukemia in children with
down syndrome.","Lundin C(1), Hjorth L, Behrendtz M, Nordgren A, Palmqvist L, Andersen MK,
Biloglav A, Forestier E, Paulsson K, Johansson B.","Author information: 
(1)Department of Clinical Genetics, University and Regional Laboratories, Skåne
University Hospital, Lund University, Sweden. catarina.lundin@med.lu.se","Previous cytogenetic studies of myeloid and acute lymphoblastic leukemias in
children with Down syndrome (ML-DS and DS-ALL) have revealed significant
differences in abnormality patterns between such cases and acute leukemias in
general. Also, certain molecular genetic aberrations characterize DS-related
leukemias, such as GATA1 mutations in ML-DS and deregulation of the CRLF2 gene in
DS-ALL. Whether microdeletions/microduplications also vary between DS and non-DS 
cases is presently unclear. To address this issue, we performed single nucleotide
polymorphism array analyses of eight pediatric ML-DS and 17 B-cell precursor
DS-ALL. In the ML-DS cases, a total of 29 imbalances (20 gains and nine losses)
and two partial uniparental isodisomies (pUPDs) were detected. None of the 11
small (defined as <10 Mb) imbalances were recurrent, nor were the pUPDs, whereas 
of the 18 large aberrations, three were recurrent-dup(1q), +8 and +21. In
contrast, several frequent changes were identified in the DS-ALL cases, which
harbored 82 imbalances (30 gains and 52 losses) and four pUPDs. Of the 40 large
changes, 28 were gains and 12 losses, with +X, dup(Xq), dup(1q), del(7p),
dup(8q), del(9p), dup(9p), del(12p), dup(17q), and +21 being recurrent. Of the 40
microdeletions identified, several targeted specific genes, with the following
being repeatedly deleted: BTG1 and CDKN2A/B (29% of cases), ETV6, IKZF1, PAX5 and
SERP2 (18%), and BTLA, INPP4B, P2RY8, and RB1 (12%). Loss of the SERP2 and INPP4B
genes, encoding the stress-associated endoplasmic reticulum protein family member
2 and the inositol polyphosphate 4-phosphatase-II, respectively, has previously
never been implicated in leukemia. Although deletions of the other genes have
been associated with ALL, the high frequency of BTG1 loss is a novel finding.
Such deletions may characterize a clinical subgroup of DS-ALL, comprising mainly 
boys with a high median age. In conclusion, ML-DS and DS-ALL are genetically
distinct, with mainly gains in ML-DS and deletions in DS-ALL. Furthermore, DS-ALL
is characterized by several recurrent gene deletions, with BTG1 loss being
particularly frequent.","Copyright © 2011 Wiley-Liss, Inc.","DOI: 10.1002/gcc.20944 
PMID: 22072402  [Indexed for MEDLINE]"
"6. Blood. 2011 Jun 23;117(25):6848-55. doi: 10.1182/blood-2011-01-329961. Epub 2011 
Apr 28.","Genomic characterization implicates iAMP21 as a likely primary genetic event in
childhood B-cell precursor acute lymphoblastic leukemia.","Rand V(1), Parker H, Russell LJ, Schwab C, Ensor H, Irving J, Jones L, Masic D,
Minto L, Morrison H, Ryan S, Robinson H, Sinclair P, Moorman AV, Strefford JC,
Harrison CJ.","Author information: 
(1)Northern Institute for Cancer Research, Newcastle University, Newcastle upon
Tyne, UK.","Intrachromosomal amplification of chromosome 21 (iAMP21) defines a distinct
subgroup of childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL)
that has a dismal outcome when treated with standard therapy. For improved
diagnosis and risk stratification, the initiating genetic events need to be
elucidated. To investigate the genetic basis of BCP-ALL, genomes of 94 iAMP21
patients were interrogated by arrays, FISH, and multiplex ligation-dependent
probe amplification. Most copy number alterations targeted chromosome 21,
reinforcing the complexity of this chromosome. The common region of amplification
on chromosome 21 was refined to a 5.1-mb region that included RUNX1, miR-802, and
genes mapping to the Down syndrome critical region. Recurrent abnormalities
affecting genes in key pathways were identified: IKZF1 (22%), CDKN2A/B (17%),
PAX5 (8%), ETV6 (19%), and RB1 (37%). Investigation of clonal architecture
provided evidence that these abnormalities, and P2RY8-CRLF2, were secondary to
chromosome 21 rearrangements. Patient outcome was uniformly poor with standard
therapy irrespective of the presence or absence of these changes. This study has 
provided evidence that chromosome 21 instability is the only anomaly among those 
so far investigated that is common to all iAMP21 patients, and therefore the
initiating event is likely to be found among the complex structural
rearrangements of this abnormal chromosome.","DOI: 10.1182/blood-2011-01-329961 
PMID: 21527530  [Indexed for MEDLINE]"
"7. Blood. 2011 Feb 17;117(7):2129-36. doi: 10.1182/blood-2010-07-297135. Epub 2010
Nov 24.","Demographic, clinical, and outcome features of children with acute lymphoblastic 
leukemia and CRLF2 deregulation: results from the MRC ALL97 clinical trial.","Ensor HM(1), Schwab C, Russell LJ, Richards SM, Morrison H, Masic D, Jones L,
Kinsey SE, Vora AJ, Mitchell CD, Harrison CJ, Moorman AV.","Author information: 
(1)Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research,
Newcastle University, Newcastle-upon-Tyne, UK.","Erratum in
    Blood. 2011 May 5;117(18):5009.","Comment in
    Blood. 2011 Feb 17;117(7):2081-2.","Deregulated expression of CRLF2 (CRLF2-d) arises via its juxtaposition to the
IGH@ enhancer or P2RY8 promoter. Among 865 BCP-ALL children treated on MRC ALL97,
52 (6%) had CRLF2-d, but it was more prevalent among Down syndrome patients
(54%). P2RY8-CRLF2 (n = 43) was more frequent than IGH@-CRLF2 (n = 9). CRLF2-d
was not associated with age, sex, or white cell count, but IGH@-CRLF2 patients
were older than P2RY8-CRLF2 patients (median 8 vs 4 years, P = .0017). Patients
with CRLF2-d were more likely to present with enlarged livers and spleens (38% vs
18%, P < .001). CRLF2-d was not seen in conjunction with established chromosomal 
translocations but 6 (12%) cases had high hyperdiploidy, and 5 (10%) had iAMP21. 
Univariate analysis suggested that CRLF2-d was associated with an inferior
outcome: (event-free survival [EFS] hazard ratio 2.27 [95% confidence interval
1.48-3.47], P < .001; OS 3.69 [2.34-5.84], P < .001). However, multivariate
analysis indicated that its effect was mediated by other risk factors such as
cytogenetics and DS status (EFS 1.45 [0.88-2.39], P = .140; OS 1.90 [1.08-3.36], 
P = .027). Although the outcome of IGH@-CRLF2 patients appeared inferior compared
with P2RY8-CRLF2 patients, the result was not significant (EFS 2.69 [1.15-6.31], 
P = .023; OS 2.86 [1.15-6.79], P = .021). Therefore, we concluded that patients
with CRLF2-d should be classified into the intermediate cytogenetic risk group.","DOI: 10.1182/blood-2010-07-297135 
PMID: 21106984  [Indexed for MEDLINE]"
"9. Blood. 2010 Jul 1;115(26):5393-7. doi: 10.1182/blood-2009-11-256131. Epub 2010
Apr 8.","Presence of the P2RY8-CRLF2 rearrangement is associated with a poor prognosis in 
non-high-risk precursor B-cell acute lymphoblastic leukemia in children treated
according to the ALL-BFM 2000 protocol.","Cario G(1), Zimmermann M, Romey R, Gesk S, Vater I, Harbott J, Schrauder A,
Moericke A, Izraeli S, Akasaka T, Dyer MJ, Siebert R, Schrappe M, Stanulla M.","Author information: 
(1)Department of Pediatrics, University Medical Center Schleswig-Holstein, Campus
Kiel, Arnold-Heller-Strasse 3, Kiel, Germany. g.cario@pediatrics.uni-kiel.de","High-level expression of the cytokine receptor-like factor 2 gene, CRLF2, in
precursor B-cell acute lymphoblastic leukemia (pB-ALL) was shown to be caused by 
a translocation involving the IGH@ locus or a deletion juxtaposing CRLF2 with the
P2RY8 promoter. To assess its possible prognostic value, CRLF2 expression was
analyzed in 555 childhood pB-ALL patients treated according to the Acute
Lymphoblastic Leukemia Berlin-Frankfurt-Münster 2000 (ALL-BFM 2000) protocol.
Besides CRLF2 rearrangements, high-level CRLF2 expression was seen in cases with 
supernumerary copies of the CRLF2 locus. On the basis of the detection of CRLF2
rearrangements, a CRLF2 high-expression group (n = 49) was defined. This group
had a 6-year relapse incidence of 31% plus or minus 8% compared with 11% plus or 
minus 1% in the CRLF2 low-expression group (P = .006). This difference was mainly
attributable to an extremely high incidence of relapse (71% +/- 19%) in
non-high-risk patients with P2RY8-CRLF2 rearrangement. The assessment of CRLF2
aberrations may therefore serve as new stratification tool in
Berlin-Frankfurt-Münster-based protocols by identifying additional high-risk
patients who may benefit from an intensified and/or targeted treatment.","DOI: 10.1182/blood-2009-11-256131 
PMID: 20378752  [Indexed for MEDLINE]"
"10. Blood. 2010 Jul 1;115(26):5312-21. doi: 10.1182/blood-2009-09-245944. Epub 2010
Feb 4.","Rearrangement of CRLF2 is associated with mutation of JAK kinases, alteration of 
IKZF1, Hispanic/Latino ethnicity, and a poor outcome in pediatric B-progenitor
acute lymphoblastic leukemia.","Harvey RC(1), Mullighan CG, Chen IM, Wharton W, Mikhail FM, Carroll AJ, Kang H,
Liu W, Dobbin KK, Smith MA, Carroll WL, Devidas M, Bowman WP, Camitta BM, Reaman 
GH, Hunger SP, Downing JR, Willman CL.","Author information: 
(1)University of New Mexico Cancer Center and Departments of Pathology and
Internal Medicine, University of New Mexico, Albuquerque, NM, USA.","Gene expression profiling of 207 uniformly treated children with high-risk
B-progenitor acute lymphoblastic leukemia revealed 29 of 207 cases (14%) with
markedly elevated expression of CRLF2 (cytokine receptor-like factor 2). Each of 
the 29 cases harbored a genomic rearrangement of CRLF2: 18 of 29 (62%) had a
translocation of the immunoglobulin heavy chain gene IGH@ on 14q32 to CRLF2 in
the pseudoautosomal region 1 of Xp22.3/Yp11.3, whereas 10 (34%) cases had a
320-kb interstitial deletion centromeric of CRLF2, resulting in a P2RY8-CRLF2
fusion. One case had both IGH@-CRLF2 and P2RY8-CRLF2, and another had a novel
CRLF2 rearrangement. Only 2 of 29 cases were Down syndrome. CRLF2 rearrangements 
were significantly associated with activating mutations of JAK1 or JAK2, deletion
or mutation of IKZF1, and Hispanic/Latino ethnicity (Fisher exact test, P < .001 
for each). Within this cohort, patients with CRLF2 rearrangements had extremely
poor treatment outcomes compared with those without CRLF2 rearrangements (35.3%
vs 71.3% relapse-free survival at 4 years; P < .001). Together, these
observations suggest that activation of CRLF2 expression, mutation of JAK
kinases, and alterations of IKZF1 cooperate to promote B-cell leukemogenesis and 
identify these pathways as important therapeutic targets in this disease.","DOI: 10.1182/blood-2009-09-245944 
PMCID: PMC2902132
PMID: 20139093  [Indexed for MEDLINE]"
"11. Blood. 2010 Feb 4;115(5):1006-17. doi: 10.1182/blood-2009-08-235408. Epub 2009
Nov 24.","Down syndrome acute lymphoblastic leukemia, a highly heterogeneous disease in
which aberrant expression of CRLF2 is associated with mutated JAK2: a report from
the International BFM Study Group.","Hertzberg L(1), Vendramini E, Ganmore I, Cazzaniga G, Schmitz M, Chalker J,
Shiloh R, Iacobucci I, Shochat C, Zeligson S, Cario G, Stanulla M, Strehl S,
Russell LJ, Harrison CJ, Bornhauser B, Yoda A, Rechavi G, Bercovich D, Borkhardt 
A, Kempski H, te Kronnie G, Bourquin JP, Domany E, Izraeli S.","Author information: 
(1)Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical 
School, Boston, MA, USA.","We report gene expression and other analyses to elucidate the molecular
characteristics of acute lymphoblastic leukemia (ALL) in children with Down
syndrome (DS). We find that by gene expression DS-ALL is a highly heterogeneous
disease not definable as a unique entity. Nevertheless, 62% (33/53) of the DS-ALL
samples analyzed were characterized by high expression of the type I cytokine
receptor CRLF2 caused by either immunoglobulin heavy locus (IgH@) translocations 
or by interstitial deletions creating chimeric transcripts P2RY8-CRLF2. In 3 of
these 33 patients, a novel activating somatic mutation, F232C in CRLF2, was
identified. Consistent with our previous research, mutations in R683 of JAK2 were
identified in 10 specimens (19% of the patients) and, interestingly, all 10 had
high CRLF2 expression. Cytokine receptor-like factor 2 (CRLF2) and mutated Janus 
kinase 2 (Jak2) cooperated in conferring cytokine-independent growth to BaF3
pro-B cells. Intriguingly, the gene expression signature of DS-ALL is enriched
with DNA damage and BCL6 responsive genes, suggesting the possibility of B-cell
lymphocytic genomic instability. Thus, DS confers increased risk for genetically 
highly diverse ALLs with frequent overexpression of CRLF2, associated with
activating mutations in the receptor itself or in JAK2. Our data also suggest
that the majority of DS children with ALL may benefit from therapy blocking the
CRLF2/JAK2 pathways.","DOI: 10.1182/blood-2009-08-235408 
PMID: 19965641  [Indexed for MEDLINE]"
14. Leuk Lymphoma. 2007 May;48(5):978-86.,"Transforming activity of purinergic receptor P2Y, G protein coupled, 8 revealed
by retroviral expression screening.","Fujiwara S(1), Yamashita Y, Choi YL, Watanabe H, Kurashina K, Soda M, Enomoto M, 
Hatanaka H, Takada S, Ozawa K, Mano H.","Author information: 
(1)Divisions of Functional Genomics, Jichi Medical University, Tochigi, Japan.","Biphenotypic acute leukemia (BAL) is a relatively rare subtype of acute leukemia 
characterized by the presence of both myeloid and lymphoid cell surface antigens.
We have now screened for transforming genes in BAL blasts with the use of the
focus formation assay with a retroviral cDNA expression library constructed from 
malignant blasts isolated from a BAL patient. Some of the retroviral inserts
recovered from transformed foci were found to encode wild-type purinergic
receptor P2Y, G protein coupled, 8 (P2RY8). The oncogenic potential of P2RY8 was 
confirmed with the in vitro focus formation assay as well as with an in vivo
tumorigenicity assay in nude mice. A variety of luciferase-based reporter assays 
revealed that P2RY8 increased both the trans-activation activities of CREB and
Elk-1 as well as the transcriptional activities of the serum response element and
enhancer-promoter fragments of the c-Fos and c-Myc genes. Quantitation of P2RY8
mRNA in CD34(+) cells of bone marrow showed that P2RY8 expression is frequently
increased in leukemia patients, especially in those with refractory disease. Our 
data thus reveal an abundant expression of P2RY8 in leukemic cells and its
unexpected role in the pathogenesis of acute leukemia.","DOI: 10.1080/10428190701225882 
PMID: 17487742  [Indexed for MEDLINE]"
15. J Med Genet. 2004 Oct;41(10):736-42.,"Disruption of a new X linked gene highly expressed in brain in a family with two 
mentally retarded males.","Cantagrel V(1), Lossi AM, Boulanger S, Depetris D, Mattei MG, Gecz J, Schwartz
CE, Van Maldergem L, Villard L.","Author information: 
(1)Inserm U491, Faculté de Médecine de La Timone, 27, Bd. Jean Moulin, 13385
Marseille Cedex 5, France.","BACKGROUND: Mental retardation (MR) affects 2-3% of the human population and some
of these cases are genetically determined. Although several genes responsible for
MR have been identified, many cases have still not been explained.
METHODS: We have identified a pericentric inversion of the X chromosome
inv(X)(p22.3;q13.2) segregating in a family where two male carriers have severe
MR while female carriers are not affected.
RESULTS: The molecular characterisation of this inversion led us to identify two 
new genes which are disrupted by the breakpoints: KIAA2022 in Xq13.2 and P2RY8 in
Xp22.3. These genes were not previously fully characterised in humans. KIAA2022
encodes a protein which lacks significant homology to any other known protein and
is highly expressed in the brain. P2RY8 is a member of the purine nucleotide
G-protein coupled receptor gene family. It is located in the pseudo-autosomal
region of the X chromosome and is not expressed in brain.
CONCLUSIONS: Because the haploinsufficiency of P2RY8 in carrier mothers does not 
have a phenotypic consequence, we propose that the severe MR of the affected
males in this family is due to the absence of the KIAA2022 gene product. However,
screening 20 probands from X linked MR families did not reveal mutations in
KIAA2022. Nonetheless, the high expression of this gene in fetal brain and in the
adult cerebral cortex could be consistent with a role in brain development and/or
cognitive function.","DOI: 10.1136/jmg.2004.021626 
PMCID: PMC1735597
PMID: 15466006  [Indexed for MEDLINE]"
16. J Biol Chem. 1997 May 9;272(19):12583-90.,"Early expression of a novel nucleotide receptor in the neural plate of Xenopus
embryos.","Bogdanov YD(1), Dale L, King BF, Whittock N, Burnstock G.","Author information: 
(1)Department of Anatomy and Developmental Biology, University College London,
Gower Street, London WC1E 6BT, United Kingdom.","Extracellular ATP functions as a neurotransmitter and neuromodulator in the adult
nervous system, and a signaling molecule in non-neural tissue, acting either via 
ligand-gated ion channels (P2X) or G-protein-coupled receptors (P2Y). ATP can
cause an increase in intracellular Ca2+ (Ca2+i) in embryonic cells and so
regulate cell proliferation, migration, and differentiation. We have isolated a
Xenopus cDNA encoding a novel P2Y receptor, XlP2Y, which is expressed abundantly 
in developing embryos. Recombinant XlP2Y responds equally to all five naturally
occurring nucleoside triphosphates (ATP, UTP, CTP, GTP, and ITP), which elicit a 
biphasic Ca2+-dependent Cl- current (ICl,Ca) where the second phase persists for 
up to 60 min. XlP2Y also causes a continuous release of Ca2+i and a low level
persistent activation of ICl,Ca in Xenopus oocytes through the spontaneous efflux
of ATP. mRNAs for XlP2Y are expressed transiently in the neural plate and tailbud
during Xenopus development, coincident with neurogenesis. This restricted pattern
of expression and novel pharmacological features confer unique properties to
XlP2Y, which may play a key role in the early development of neural tissue.","DOI: 10.1074/jbc.272.19.12583 
PMID: 9139711  [Indexed for MEDLINE]",