Mutations of JAK2 in acute lymphoblastic leukaemias associated with Down's syndrome

Dani Bercovich, Ithamar Ganmore, Linda M. Scott, Gilad Wainreb, Yehudit Birger, Arava Elimelech, Chen Shochat, Giovanni Cazzaniga, Andrea Biondi, Giuseppe Basso, Gunnar Cario, Martin Schrappe, Martin Stanulla, Sabine Strehl, Oskar A. Haas, Georg Mann, Vera Binder, Arndt Borkhardt, Helena Kempski, Jan TrkaBella Bielorei, Smadar Avigad, Batia Stark, Owen Smith, Nicole Dastugue, Jean Pierre Bourquin, Nir Ben Tal, Anthony R. Green, Shai Izraeli*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

283 Scopus citations


Background: Children with Down's syndrome have a greatly increased risk of acute megakaryoblastic and acute lymphoblastic leukaemias. Acute megakaryoblastic leukaemia in Down's syndrome is characterised by a somatic mutation in GATA1. Constitutive activation of the JAK/STAT (Janus kinase and signal transducer and activator of transcription) pathway occurs in several haematopoietic malignant diseases. We tested the hypothesis that mutations in JAK2 might be a common molecular event in acute lymphoblastic leukaemia associated with Down's syndrome. Methods: JAK2 DNA mutational analysis was done on diagnostic bone marrow samples obtained from 88 patients with Down's syndrome-associated acute lymphoblastic leukaemia; and 216 patients with sporadic acute lymphoblastic leukaemia, Down's syndrome-associated acute megakaryoblastic leukaemia, and essential thrombocythaemia. Functional consequences of identified mutations were studied in mouse haematopoietic progenitor cells. Findings: Somatically acquired JAK2 mutations were identified in 16 (18%) patients with Down's syndrome-associated acute lymphoblastic leukaemia. The only patient with non-Down's syndrome-associated leukaemia but with a JAK2 mutation had an isochromosome 21q. Children with a JAK2 mutation were younger (mean [SE] age 4·5 years [0·86] vs 8·6 years [0·59], p<0·0001) at diagnosis. Five mutant alleles were identified, each affecting a highly conserved arginine residue (R683). These mutations immortalised primary mouse haematopoietic progenitor cells in vitro, and caused constitutive Jak/Stat activation and cytokine-independent growth of BaF3 cells, which was sensitive to pharmacological inhibition with JAK inhibitor I. In modelling studies of the JAK2 pseudokinase domain, R683 was situated in an exposed conserved region separated from the one implicated in myeloproliferative disorders. Interpretation: A specific genotype-phenotype association exists between the type of somatic mutation within the JAK2 pseudokinase domain and the development of B-lymphoid or myeloid neoplasms. Somatically acquired R683 JAK2 mutations define a distinct acute lymphoblastic leukaemia subgroup that is uniquely associated with trisomy 21. JAK2 inhibitors could be useful for treatment of this leukaemia. Funding: Israel Trade Ministry, Israel Science Ministry, Jewish National Fund UK, Sam Waxman Cancer Research Foundation, Israel Science Foundation, Israel Cancer Association, Curtis Katz, Constantiner Institute for Molecular Genetics, German-Israel Foundation, and European Commission FP6 Integrated Project EUROHEAR.

Original languageEnglish
Pages (from-to)1484-1492
Number of pages9
JournalThe Lancet
Issue number9648
StatePublished - 2008


FundersFunder number
Constantiner Institute for Molecular Genetics
European Commission FP6LSHG-CT-20054-512063
German–Israel Foundation
Israel Science Ministry
Israel Trade Ministry
Samuel Waxman Cancer Research Foundation
Jewish National Fund
Israel Cancer Association
Israel Science Foundation


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