A novel activating, germline JAK2 mutation, JAK2R₅₆₄Q, causes familial essential thrombocytosis

Along with the most common mutation, JAK2V₆₁₇F, several other acquired JAK2 mutations have now been shown to contribute to the pathogenesis of myeloproliferative neoplasms (MPNs). However, here we describe for the first time a germline mutation that leads to familial thrombocytosis that involves a residue other than Val₆₁₇. The novel mutation JAK2R₅₆₄Q, identified in a family with autosomal dominant essential thrombocythemia, increased cell growth resulting from suppression of apoptosis in Ba/F3-MPL cells. Although JAK2R₅₆₄Q and JAK2V₆₁₇F have similar levels of increased kinase activity, the growth-promoting effects of JAK2R ₅₆₄Q are much milder than those of JAK2V₆₁₇F because of at least 2 counter regulatory mechanisms. Whereas JAK2V₆₁₇F can escape regulation by the suppressor of cytokine signaling 3 and p27/Kip1, JAK2R ₅₆₄Q-expressing cells cannot. Moreover, JAK2R₅₆₄Q- expressing cells are much more sensitive to the JAK inhibitor, ruxolitinib, than JAK2V₆₁₇F-expressers, suggesting that lower doses of this drug may be effective in treating patients with MPNs associated with alternative JAK2 mutations, allowing many undesirable adverse effects to be avoided. This work provides a greater understanding of the cellular effects of a non-JAK2V ₆₁₇F, MPN-associated JAK2 mutation; provides insights into new treatment strategies for such patients; and describes the first case of familial thrombosis caused by a JAK2 residue other than Val₆₁₇.