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

Authors: Marty, C  Saint-Martin, C  Pecquet, C  Grosjean, S  Saliba, J  Mouton, C  Leroy, E  Harutyunyan, AS  Abgrall, JF  Favier, R  Toussaint, A  Solary, E  Kralovics, R  Constantinescu, SN  Najman, A  Vainchenker, W  Plo, I  Bellanne-Chantelot, C 
Citation: Marty C, etal., Blood. 2014 Feb 27;123(9):1372-83. doi: 10.1182/blood-2013-05-504555. Epub 2014 Jan 7.
Pubmed: (View Article at PubMed) PMID:24398328
DOI: Full-text: DOI:10.1182/blood-2013-05-504555

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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CRRD ID: 10449375
Created: 2015-12-23
Species: All species
Last Modified: 2015-12-23
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.