Loss of K607 and E877 interaction is a key reason for JAK2 K607N mutation caused acute myeloid leukemia
Loss of K607 and E877 interaction is a key reason for JAK2 K607N mutation caused acute myeloid leukemia
复制标题
K607和E877相互作用的丧失是JAK2 K607N突变引起急性髓系白血病的关键原因。
DOI：
10.1016/j.ijbiomac.2018.11.280
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发表时间：
2019-03-01
影响因子：
8.2
通讯作者：
Xu, Kai-Lin
中科院分区：
文献类型：
--
作者：
Wu, Qing-Yun;Ma, Meng-Meng;Xu, Kai-Lin
Oncogenic activation of tyrosine kinase signaling pathway is recurrent in human leukemia. The acquired Janus kinase 2 (JAK2) K607N somatic mutation was detected in about 6.8% of acute myeloid leukemia (AML) patients. However, roles of JAK2 K607N mutation in the leukemogenesis of AML remain unclear. In this study, loss of interaction between K607 and E877 was identified as key reasons for JAK2 K607N mutation constitutive activation. JAK2 K607N and mutations (K607A, K607G and E877A) abolished the K607 and E877 interaction caused JAK2 constitutive activation. While, mutations (K607R, E877D) repairing this interaction reduced K607N mutation's activity. Furthermore, our studies showed that disruption of K607 and E877 interaction abolished JH1/JH2 domains' interactions and led to JAK2 constitutive activation. More importantly, JAK2 K607N and mutations disrupted this interaction enhanced JAK2-STAT5 pathway activation and the proliferation of Ba/F3 cells. Thus our studies provide clues in understanding the leukemogenesis of JAK2 K607N mutation in AML. (C) 2018 Elsevier B.V. All rights reserved.
