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Germ-line JAK2 mutations in the kinase domain are responsible for hereditary thrombocytosis and are resistant to JAK2 and HSP90 inhibitors.

Authors
  • Marty, Caroline
  • Saint-Martin, Cécile
  • Pecquet, Christian
  • Grosjean, Sarah
  • Saliba, Joseph
  • Mouton, Céline
  • Leroy, Emilie
  • Harutyunyan, Ashot S
  • Abgrall, Jean-François
  • Favier, Rémi
  • Toussaint, Aurélie
  • Solary, Eric
  • Kralovics, Robert
  • Constantinescu, Stefan N
  • Najman, Albert
  • Vainchenker, William
  • Plo, Isabelle
  • Bellanné-Chantelot, Christine
Type
Published Article
Journal
Blood
Publisher
American Society of Hematology
Publication Date
Feb 27, 2014
Volume
123
Issue
9
Pages
1372–1383
Identifiers
DOI: 10.1182/blood-2013-05-504555
PMID: 24398328
Source
Medline
License
Unknown

Abstract

The main molecular basis of essential thrombocythemia and hereditary thrombocytosis is acquired, and germ-line-activating mutations affect the thrombopoietin signaling axis. We have identified 2 families with hereditary thrombocytosis presenting novel heterozygous germ-line mutations of JAK2. One family carries the JAK2 R867Q mutation located in the kinase domain, whereas the other presents 2 JAK2 mutations, S755R/R938Q, located in cis in both the pseudokinase and kinase domains. Expression of Janus kinase 2 (JAK2) R867Q and S755R/R938Q induced spontaneous growth of Ba/F3-thrombopoietin receptor (MPL) but not of Ba/F3-human receptor of erythropoietin cells. Interestingly, both Ba/F3-MPL cells expressing the mutants and platelets from patients displayed thrombopoietin-independent phosphorylation of signal transducer and activator of transcription 1. The JAK2 R867Q and S755R/R938Q proteins had significantly longer half-lives compared with JAK2 V617F. The longer half-lives correlated with increased binding to the heat shock protein 90 (HSP90) chaperone and with higher MPL cell-surface expression. Moreover, these mutants were less sensitive to JAK2 and HSP90 inhibitors than JAK2 V617F. Our results suggest that the mutations in the kinase domain of JAK2 may confer a weak activation of signaling specifically dependent on MPL while inducing a decreased sensitivity to clinically available JAK2 inhibitors.

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