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DOWN'S Syndrome Acute Lymphoblastic LEUKEMIA: A HIGHLY Heterogeneous DISEASE DRIVEN by an Aberrant CRLF2/JAK2 Cooperation – A REPORT FROM the Ibfm-STUDY GROUP.
Journal article

DOWN'S Syndrome Acute Lymphoblastic LEUKEMIA: A HIGHLY Heterogeneous DISEASE DRIVEN by an Aberrant CRLF2/JAK2 Cooperation – A REPORT FROM the Ibfm-STUDY GROUP.

  • Hertzberg, Libi Cancer Research Center, Chaim Sheba Medical Center, Ramat Gan, Israel,
  • Vendramini, Elena Pediatrcs, University of Padova, Padova, Italy,
  • Ganmore, Ithamar Chaim Sheba Medical Center, Israel,
  • Cazzaniga, Giovanni Pediatric Clinic University of Milan Bicocca, M.Tettamanti Research Center, Monza, Italy,
  • Schmitz, Maike Department of Pediatric Oncology,, University Children's Hospital, University of Zurich,
  • Shiloh, Ruth Chaim Sheba Medical Center, Israel,
  • Chalker, Jane Institue of Child Health, UCL,
  • Iacobucci, Ilaria Department of Hematology/Oncology ‘L. and A. Seràgnoli‘, University of Bologna, Bologna, Italy,
  • Shochat, Chen Migal–Galilee Biotechnology Center, Israel,
  • Zeligson, Sharon Cancer Research Center, Chaim Sheba Medical Center, Ramat Gan, Israel,
  • Cario, Gunnar Pediatrics, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany,
  • Stanulla, Martin Dpt of Pediatrics, University Hospital Schleswig-Holstein, Kiel, Germany,
  • Strehl, Sabine Ccri, Children Cancer Research Institute St Anna Kinderspital, Vienna, Austria,
  • Russel, Lisa J Northern Institute for Cancer Research, NewCastle, United Kingdom,
  • Harrison, Christine Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom,
  • Bornhauser, Beat Department of Pediatric Oncology,, University Children's Hospital, University of Zurich,
  • Yoda, Akinori Dana-Farber Cancer Institute, Boston, MA, USA,
  • Rechavi, Gideon Cancer Research Center, Sheba Medical Center, Tel-Hashomer, Israel,
  • Bercovich, Dani Migal–Galilee Biotechnology Center, Israel,
  • Borkardt, Arndt Heinrich Heine University, Dusseldorf, Germany,
  • Kempski, Helena Pediatric Cytogenetics Malignancy Unit, Great Ormond Street Hospital, London,
  • Kronnie, Geertruy te Pediatrcs, University of Padova, Padova, Italy,
  • Bourquin, Jean-Pierre Paediatric Haematology/Oncology, University of Zurich, Zurich, Switzerland,
  • Domany, Eytan Weizmann Institute of Sciences,
  • Izraeli, Shai Chaim Sheba Medical Center, Ramat Gan, Israel
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Published in:
  • Blood. - American Society of Hematology. - 2009, vol. 114, no. 22, p. 11-11
Immunology
Cell Biology
Biochemistry
Hematology
English Abstract
Abstract 11


Children with Down's Syndrome (DS) have an increased risk for acute lymphoblastic leukemia (ALL). We have previously identified somatic mutations in R683 of JAK2 in 20% of DS-ALLs (Bercovich et al, Lancet 2008;372:1484). However the cooperating cytokine receptor and other molecular features have been obscured. Here we report that gene expression analysis reveals that DS-ALL is a highly heterogeneous disease not definable as unique ALL subtype. However, 62% (33 of 53) of the DS-ALL samples analyzed were characterized by aberrant expression of the type I cytokine receptor CRLF2 caused by two types of genomic aberrations. CRLF2 encodes one chain of the heterodimeric receptor of the TSLP cytokine involved in inflammation and lymphoid development and has been recently reported to be involved in translocations to the IgH locus or micro-deletions in 3% of ALLs in children without DS. We have confirmed its cell surface expression on primary DS-ALL cells by Flow cytometry analysis. Consisting with a possible role of CRLF2 as a cytokine receptor, all specimens with the R683 mutated JAK2 had high CRLF2 expression. We further show that CRLF2 and R683 mutated JAK2 cooperate in conferring cytokine independent growth of pro-B cells. Furthermore in 3 of 23 DS-ALL patients with wt. JAK2 we identified a novel activating somatic mutation in CRLF2 replacing the juxta-membrane F232 with Cystein. Mutated CRLF2 but not wild type CRLF2 conferred cytokine independent growth of BaF3 cells associated with phosphorylation of STAT5. Aberrant expression of CRLF2 was also associated with a younger age at diagnosis and worse prognosis. Intriguingly, bioinformatic analysis revealed that gene expression of DS-ALLs is enriched with DNA damage and BCL6 responsive genes suggesting the possibility that DS is associated with B-cell lymphocytic genomic instability leading to the genomic aberrations activating CRLF2. Thus DS confers increased risk for genetically highly diverse ALLs with frequent somatic anomaly in CRLF2, whose higher expression further selects for the activating mutations in itself or in JAK2 (figure). Our data also suggests that the majority of DS children with ALL may benefit from therapy blocking the CRLF2/JAK2 pathway.


Disclosures:
No relevant conflicts of interest to declare.
Language
  • English
Open access status
closed
Identifiers
Persistent URL
https://sonar.ch/global/documents/72228
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