Germline JAK2 Mutations In The Kinase Domain Are Responsible For Hereditary Thrombocytosis and Are Resistant To JAK2 and HSP90 Inhibitors

Abstract

The main molecular basis of essential thrombocytemia and hereditary thrombocytosis are acquired and germline activating mutations affecting the thrombopoietin signaling axis, respectively. We have identified two families with hereditary thrombocytosis presenting novel heterozygous germline mutations of JAK2. One family carries the JAK2 R867Q mutation located in the kinase domain, while the other presents two JAK2 mutations, S755R/R938Q, located in cis in both the pseudokinase and kinase domains. Expression of JAK2 R867Q and S755R/R938Q induced spontaneous growth of Ba/F3-MPL but not of Ba/F3-EPOR cells. Interestingly, both Ba/F3-MPL cells expressing the mutants and platelets from patients displayed a TPO-independent phosphorylation of STAT1. JAK2 R867Q and S755R/R938Q, compared to JAK2 V617F, had significantly longer half-lives correlating with an increased MPL cell surface expression. Moreover, these mutations conferred a resistance to JAK2 and HSP90 inhibitors compared to 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 resistance to clinically available JAK2 inhibitors. Disclosures:No relevant conflicts of interest to declare.