A novel activating, germline JAK2 mutation, JAK2R564Q, causes familial essential thrombocytosis
A novel activating, germline JAK2 mutation, JAK2R564Q, causes familial essential thrombocytosis
复制标题
DOI：
10.1182/blood-2012-12-473777
复制
发表时间：
2014-02-13
期刊：
影响因子：
20.3
通讯作者：
Hitchcock, Ian S.
中科院分区：
文献类型：
--
作者：
Etheridge, S. Leah;Cosgrove, Megan E.;Hitchcock, Ian S.
除了最常见的JAK2V(617)F突变外，其他几个获得性JAK2突变现已被证明与骨髓增生性肿瘤(MPN)的发病有关。然而，在这里，我们首次描述了一种导致家族性血小板增多症的生殖系突变，该突变涉及Val以外的残基(617)。新的突变JAK2R(564)Q，在一个常染色体显性遗传性原发性血小板增多症家族中被发现，通过抑制细胞凋亡而促进细胞生长。虽然JAK2R(564)Q和JAK2V(617)F具有相似的增加的激酶活性，但JAK2R(564)Q的促生长作用比JAK2V(617)F弱得多，这是因为至少有两种相反的调节机制。JAK2V(617)F可以逃脱细胞因子信号转导3和p27/Kip1抑制因子的调控，而JAK2R(564)Q表达细胞则不能。此外，JAK2R(564)Q表达细胞对JAK抑制剂ruxolitinib的敏感性远高于JAK2V(617)F表达载体，这表明较低剂量的这种药物可能有效地治疗与JAK2替代突变相关的MPN患者，从而避免了许多不良反应。这项工作有助于更好地了解非JAK2V(617)F、MPN相关JAK2突变的细胞效应；为此类患者提供新的治疗策略；并描述了首例由Val(617)以外的JAK2残基引起的家族性血栓形成。
Along with the most common mutation, JAK2V(617)F, 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 Val(617). The novel mutation JAK2R(564)Q, identified in a family with autosomal dominant essential thrombocythemia, increased cell growth resulting from suppression of apoptosis in Ba/F3-MPL cells. Although JAK2R(564)Q and JAK2V(617)F have similar levels of increased kinase activity, the growth-promoting effects of JAK2R(564)Q are much milder than those of JAK2V(617)F because of at least 2 counter regulatory mechanisms. Whereas JAK2V(617)F can escape regulation by the suppressor of cytokine signaling 3 and p27/Kip1, JAK2R(564)Q-expressing cells cannot. Moreover, JAK2R(564)Q-expressing cells are much more sensitive to the JAK inhibitor, ruxolitinib, than JAK2V(617)F-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(617)F, 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 Val(617).