The V617F mutation in the JH2 domain of JAK2 is an oncogenic driver in several myeloproliferative neoplasms (MPNs), including essential thrombocythemia, myelofibrosis, and polycythemia vera (PV). Other mutations in JAK2 have been identified in MPNs, most notably exon 12 mutations in PV. Here, we describe a novel recurrent mutation characterized by a common 4-amino acid deletion and variable 1-amino acid insertion (Leu583-Ala586DelInsSer/Gln/Pro) within the JH2 domain of JAK2. All four affected patients had eosinophilia, and both patients with Leu583-Ala586DelInsSer fulfilled diagnostic criteria of both PV and chronic eosinophilic leukemia (CEL). Computational and functional studies revealed that Leu583-Ala586DelInsSer (herein referred to as JAK2ex13InDel) deregulates JAK2 through a mechanism similar to JAK2V617F, activates STAT5 and ERK and transforms parental Ba/F3 cells to growth factor independence. In contrast to JAK2V617F, JAK2ex13InDel does not require an exogenous homodimeric type 1 cytokine receptor to transform Ba/F3 cells, and is capable of activating β common chain family cytokine receptor (IL-3R, IL-5R, granulocyte-macrophage colony stimulating factor receptor) signaling in the absence of ligand, with the maximum effect observed for IL-5R, consistent with the clinical phenotype of eosinophilia. Recognizing this new PV/CEL overlap MPN has significant clinical implications, as both PV and CEL patients are at high risk for thrombosis, and concomitant cytoreduction of red cells, neutrophils and eosinophils may be required for prevention of thromboembolic events. Targeted next-generation sequencing for genes recurrently mutated in myeloid malignancies in patients with unexplained eosinophilia may reveal additional cases of Leu583-Ala586DelInsSer/Gln/Pro, allowing for complete characterization of this unique MPN.

中文翻译：

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JAK2ex13InDel 驱动致癌转化并与慢性嗜酸性粒细胞白血病和真性红细胞增多症相关


JAK2 JH2 结构域中的 V617F 突变是多种骨髓增殖性肿瘤 (MPN) 的致癌驱动因素，包括原发性血小板增多症、骨髓纤维化和真性红细胞增多症 (PV)。 MPN 中还发现了 JAK2 的其他突变，最引人注目的是 PV 中的外显子 12 突变。在这里，我们描述了一种新的复发突变，其特征是 JAK2 的 JH2 结构域内常见的 4 个氨基酸缺失和可变的 1 个氨基酸插入 (Leu583-Ala586DelInsSer/Gln/Pro)。所有四名受影响的患者均患有嗜酸性粒细胞增多，并且两名 Leu583-Ala586DelInsSer 患者均符合 PV 和慢性嗜酸性粒细胞白血病 (CEL) 的诊断标准。计算和功能研究表明，Leu583-Ala586DelInsSer（本文称为 JAK2ex13InDel）通过类似于 JAK2V617F 的机制解除 JAK2 的调节，激活 STAT5 和 ERK 并将亲代 Ba/F3 细胞转化为生长因子独立性。与JAK2V617F相比，JAK2ex13InDel不需要外源同源二聚体1型细胞因子受体来转化Ba/F3细胞，并且能够激活β共链家族细胞因子受体（IL-3R、IL-5R、粒细胞-巨噬细胞集落刺激因子受体） ) 在没有配体的情况下信号传导，观察到 IL-5R 的最大效应，与嗜酸性粒细胞增多的临床表型一致。认识到这种新的 PV/CEL 重叠 MPN 具有重要的临床意义，因为 PV 和 CEL 患者均处于血栓形成的高风险，并且可能需要同时进行红细胞、中性粒细胞和嗜酸性粒细胞细胞减灭以预防血栓栓塞事件。 对不明原因嗜酸性粒细胞增多症患者的骨髓恶性肿瘤中反复突变的基因进行下一代靶向测序可能会揭示更多 Leu583-Ala586DelInsSer/Gln/Pro 病例，从而能够完整表征这种独特的 MPN。