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Down Syndrome Acute Lymphoblastic Leukemia, a Highly Heterogeneous

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Down Syndrome Acute Lymphoblastic Leukemia, a Highly Heterogeneous Hertzberg, L; 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, L J; Harrison, C J; Bornhauser, B; Yoda, A; Rechavi, G; Bercovich, D; Borkhardt, A; Kempski, H; te Kronnie, G; Bourquin, J P; Domany, E; Izraeli, S (2010). 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. Blood, 115(5):1006-1017. University of Zurich Postprint available at: Zurich Open Repository and Archive http://www.zora.uzh.ch Posted at the Zurich Open Repository and Archive, University of Zurich. http://www.zora.uzh.ch Winterthurerstr. 190 Originally published at: CH-8057 Zurich Blood 2010, 115(5):1006-1017. http://www.zora.uzh.ch Year: 2010 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; 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, L J; Harrison, C J; Bornhauser, B; Yoda, A; Rechavi, G; Bercovich, D; Borkhardt, A; Kempski, H; te Kronnie, G; Bourquin, J P; Domany, E; Izraeli, S Hertzberg, L; 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, L J; Harrison, C J; Bornhauser, B; Yoda, A; Rechavi, G; Bercovich, D; Borkhardt, A; Kempski, H; te Kronnie, G; Bourquin, J P; Domany, E; Izraeli, S (2010). 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. Blood, 115(5):1006-1017. Postprint available at: http://www.zora.uzh.ch Posted at the Zurich Open Repository and Archive, University of Zurich. http://www.zora.uzh.ch Originally published at: Blood 2010, 115(5):1006-1017. 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 Abstract 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. LYMPHOID NEOPLASIA 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 *Libi Hertzberg,1-3 *Elena Vendramini,4 *Ithamar Ganmore,1,2 Gianni Cazzaniga,5 Maike Schmitz,6 Jane Chalker,7 Ruth Shiloh,1 Ilaria Iacobucci,8 Chen Shochat,1,2,9 Sharon Zeligson,1 Gunnar Cario,10 Martin Stanulla,10 Sabine Strehl,11 Lisa J. Russell,12 Christine J. Harrison,12 Beat Bornhauser,6 Akinori Yoda,13 Gideon Rechavi,1,2 Dani Bercovich,9 Arndt Borkhardt,14 Helena Kempski,7 †Geertruy te Kronnie,4 †Jean-Pierre Bourquin,6 †Eytan Domany,3 and †Shai Izraeli1,2 1Pediatric Hemato-Oncology and the Cancer Research Center, Sheba Medical Center, Tel Hashomer, Ramat-Gan, Israel; 2Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; 3Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot, Israel; 4Hemato-Oncology Laboratory, Department of Pediatrics, University of Padova, Padova, Italy; 5Centro Ricerca Tettamanti, Clinica Paediatrica Universita` di Milano-Bicocca, Ospedale San Gerardo, Monza, Italy; 6Department of Pediatric Oncology, University Children’s Hospital, University of Zurich, Zurich, Switzerland; 7Paediatric Malignancy Cytogenetics Unit, Camelia Botnar Laboratories, Great Ormond Street Hospital & Institute of Child Health, London, United Kingdom; 8Department of Hematology/Oncology L. and A. Sera`gnoli, University of Bologna, Bologna, Italy; 9Human Molecular Genetics and Pharmacogenetics Laboratory, Migal–Galilee Biotechnology Center, Kiryat Shmona, and Tel-Hai Academic College, Tel Hai, Israel; 10Department of Pediatrics, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany; 11Children’s Cancer Research Institute, St Anna Kinderkrebsforschung, Vienna, Austria; 12Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle, United Kingdom; 13Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; and 14Clinic of Pediatric Oncology, Hematology, and Clinical Immunology, Children’s University Hospital, Heinrich Heine University, Du¨sseldorf, Germany We report gene expression and other analy- chimeric transcripts P2RY8-CRLF2.In3of enriched with DNA damage and BCL6 re- ses to elucidate the molecular characteris- these 33 patients, a novel activating somatic sponsive genes, suggesting the possibility tics of acute lymphoblastic leukemia (ALL) mutation, F232C in CRLF2, was identified. of B-cell lymphocytic genomic instability. in children with Down syndrome (DS). We Consistent with our previous research, mu- Thus, DS confers increased risk for geneti- find that by gene expression DS-ALL is a tations in R683 of JAK2 were identified in cally highly diverse ALLs with frequent over- highly heterogeneous disease not definable 10 specimens (19% of the patients) and, expression of CRLF2, associated with acti- as a unique entity. Nevertheless, 62% (33/53) interestingly, all 10 had high CRLF2 expres- vating mutations in the receptor itself or in of the DS-ALL samples analyzed were char- sion. Cytokine receptor-like factor 2 (CRLF2) JAK2. Our data also suggest that the major- acterized by high expression of the type I and mutated Janus kinase 2 (Jak2) cooper- ity of DS children with ALL may benefit from cytokine receptor CRLF2 caused by either ated in conferring cytokine-independent therapy blocking the CRLF2/JAK2 path- immunoglobulin heavy locus (IgH@) translo- growth to BaF3 pro-B cells. Intriguingly, the ways. (Blood. 2010;115:1006-1017) cations or by interstitial deletions creating gene expression signature of DS-ALL is Introduction Children with Down syndrome (DS) have a higher rate of acute To characterize additional molecular abnormalities in DS-ALL, lymphoblastic leukemia (DS-ALL). DS-ALLs are mostly of B-cell we performed genomic analysis of a large group of DS-ALLs. This precursor (BCP) origin and similar in the age of diagnosis and analysis reveals, next to a striking heterogeneity of these leuke- immunophenotype to high hyperdiploid (HD) or TEL-AML1 ALLs,1 mias, an aberrant expression of the cytokine receptor CRLF2 in the 2 most common genetic subtypes of childhood ALL. Given that 62% of the patients, associated with somatic activating mutations these cytogenetic abnormalities are less frequent in DS-ALL,2 the in JAK2 or in the receptor itself. existence of unique collaborating somatic genetic events in DS- ALL, similar to the GATA1 mutation in DS-acute megakaryoblastic leukemia,3 has been postulated. Methods We and others reported the presence of somatic activating mutations in JAK2 in approximately 20% of DS-ALLs.4-6 Similar mutations are Patient samples present in approximately 10% of high-risk ALLs in non-DS children, RNA and DNA were derived from diagnostic bone marrow samples of 7 corresponding to approximately 3% of unselected childhood ALLs. We children with DS and BCP-ALL enrolled on treatment protocols with an hypothesized that the mutated Janus kinase 2 (JAK2) may cooperate informed consent and approval of the ethics committees of all participating with a type I cytokine receptor that is aberrantly expressed in DS-ALL.4 institutions in accordance with the Declaration of Helsinki. Samples were Submitted August 5, 2009; accepted November 1, 2009. Prepublished online The online version of this article contains a data supplement. as Blood First Edition paper, November 24, 2009; DOI 10.1182/blood-2009-08- The publication costs of this article were defrayed in part by page charge 235408. payment. Therefore, and solely to indicate this fact, this article is hereby *L.H., E.V., and I.G. are co–first authors. marked ‘‘advertisement’’ in accordance with 18 USC section 1734. †G.t.K., J.-P.B., E.D., and S.I. are co–senior authors. © 2010 by The American Society of Hematology 1006 BLOOD, 4 FEBRUARY 2010 ⅐ VOLUME 115, NUMBER 5 BLOOD, 4 FEBRUARY 2010 ⅐ VOLUME 115, NUMBER 5 GENOMIC ANALYSIS OF DS-ALL 1007 Table 1. Description of the gene expression datasets analyzed No. samples Dataset symbol Total DS-ALL HD TEL-AML1 Other Platform AIEOP* 97 25 26 29 4 E2A-PBX1, 6 MLL, 7 BCR-ABL Affymetrix HG-U133 Plus 2.0 ICH 15 6 5 4 Affymetrix HG-U133 Plus 2.0 BFM8* ϩ St Jude10† 36 7 12 17 Affymetrix HG-U133A IL† 27 11 10 6 Affymetrix Exon 1.0 ST AIEOP indicates Associazione Italiana Ematologia Oncologia Pediatrica; ICH, Institute Child Health; BFM, Berlin-Frankfurt-Munster; and IL, Israel.
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