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

Marty, Caroline;Saint-Martin, Cécile;Pecquet, Christian;Grosjean, Sarah;Bellanné-Chantelot, Christine;et.al.
(2014) Blood — Vol. 123, n° 9, p. 1372-1383 (2014)

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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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Marty, C., Saint-Martin, C., Pecquet, C., Grosjean, S., Saliba, J., Mouton, C., Leroy, E., Harutyunyan, A. S., Abgrall, J.-F., Favier, R., Toussaint, A., Solary, E., Kralovics, R., Constantinescu, S., Najman, A., Vainchenker, W., Plo, I., & Bellanné-Chantelot, C. (2014). Germ-line JAK2 mutations in the kinase domain are responsible for hereditary thrombocytosis and are resistant to JAK2 and HSP90 inhibitors. Blood, 123(9), 1372-1383. https://doi.org/10.1182/blood-2013-05-504555 (Original work published 2014)