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

Bercovich, Dani, Ganmore, Ithamar, Scott, Linda M., Wainreb, Gilad, Birger, Yehudit, Elimelech, Arava, Chen, Shochat, Cazzaniga, Giovanni, Biondi, Andrea, Basso, Giuseppe, Cario, Gunnar, Schrappe, Martin, Stanulla, Martin, Strehl, Sabine, Haas, Oskar A., Mann, Georg, Binder, Vera, Borkhardt, Arndt, Kempski, Helena, Trka, Jan, Bielorei, Bella, Avigad, Smadar, Stark, Batia, Smith, Owen, Dastugue, Nicole, Bourquin, Jean-Pierre, Ben Tal, Nir, Green, Anthony R. and Izraeli, Shai (2008) Mutations of JAK2 in acute lymphoblastic leukaemias associated with Down's syndrome. Lancet, 372 9648: 1484-1492. doi:10.1016/S0140-6736(08)61341-0

Author Bercovich, Dani
Ganmore, Ithamar
Scott, Linda M.
Wainreb, Gilad
Birger, Yehudit
Elimelech, Arava
Chen, Shochat
Cazzaniga, Giovanni
Biondi, Andrea
Basso, Giuseppe
Cario, Gunnar
Schrappe, Martin
Stanulla, Martin
Strehl, Sabine
Haas, Oskar A.
Mann, Georg
Binder, Vera
Borkhardt, Arndt
Kempski, Helena
Trka, Jan
Bielorei, Bella
Avigad, Smadar
Stark, Batia
Smith, Owen
Dastugue, Nicole
Bourquin, Jean-Pierre
Ben Tal, Nir
Green, Anthony R.
Izraeli, Shai
Title Mutations of JAK2 in acute lymphoblastic leukaemias associated with Down's syndrome
Journal name Lancet   Check publisher's open access policy
ISSN 0140-6736
Publication date 2008-10-25
Sub-type Article (original research)
DOI 10.1016/S0140-6736(08)61341-0
Volume 372
Issue 9648
Start page 1484
End page 1492
Total pages 9
Place of publication London, United Kingdom
Publisher The Lancet Publishing Group
Language eng
Formatted abstract
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.

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.
Keyword Myeloproliferative disorders
Megakaryoblastic leukemia
Acquired mutations
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ
Additional Notes Publication date: 25-31 October 2008.

Document type: Journal Article
Sub-type: Article (original research)
Collection: UQ Diamantina Institute Publications
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 178 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 196 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Thu, 04 Apr 2013, 09:55:10 EST by System User on behalf of Scholarly Communication and Digitisation Service