Disruption of R867 and Y613 interaction plays key roles in JAK2 R867Q mutation caused acute leukemia
Disruption of R867 and Y613 interaction plays key roles in JAK2 R867Q mutation caused acute leukemia
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R867和Y613相互作用的破坏在JAK2 R867Q突变引起的急性白血病中起关键作用
DOI：
10.1016/j.ijbiomac.2019.06.068
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发表时间：
2019-09-01
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
Janus tyrosine kinase 2 （JAK2）介导所有血液学谱系中细胞因子受体的下游信号传导，组成性活跃的体细胞JAK2突变对急性白血病（AL）的白血病发生至关重要。JAK2 R867Q体细胞突变在AL患者的一个子集中被检测到。然而，JAK2 r867q突变在AL发病机制中的作用尚不清楚。在本研究中，同源性建模分析表明，R867和Y613之间相互作用的缺失破坏了JAK2 JH1/JH2结构域的相互作用，这是导致其激活的原因。JAK2 R867Qand突变（R867A和R867G）消除了这种相互作用，导致JAK2组成激活。而修复这种相互作用的突变（R867K, Y613E, R867K/Y613E）降低了JAK2 R867Q突变的活性。此外，我们的研究表明，R867和Y613相互作用的消除破坏了JH1/JH2结构域的相互作用，导致JAK2的组成性激活。更重要的是，突变（R867Q、R867A和R867G）破坏了这种相互作用，增强了JAK2-STAT5通路的活性和Ba/F3和MV4-11细胞的增殖。进一步研究表明，JAK2 R867Q突变促进了Ba/F3和MV4-11细胞增殖标志物的表达，抑制了分化标志物的表达。因此，我们的研究为理解AL. (C) 2019中JAK2 R867Q突变的发病机制提供了线索。
Janus tyrosine kinase 2 (JAK2) mediates downstream signaling of cytokine receptors in all hematological lineages, constitutively active somatic JAK2 mutations were important for the leukemogenesis of acute leukemia (AL). The JAK2 R867Q somatic mutation is detected in a subset of AL patients. However, roles of JAK2 R867Qmutation in the pathogenesis of AL remain unclear. In this study, homology modeling analysis showed that loss of interaction between R867 and Y613 disrupted the JAK2 JH1/JH2 domain's interactions was responsible for its activation. JAK2 R867Qand mutations (R867A and R867G) abolished this interaction caused JAK2 constitutive activation. While, mutations (R867K, Y613E, R867K/Y613E) repairing this interaction reduced JAK2 R867Q mutation's activity. Furthermore, our studies showed that abolished R867 and Y613 interaction disrupted JH1/JH2 domains' interactions and led to JAK2 constitutive activation. More importantly, mutations (R867Q R867A and R867G) disrupted this interaction enhanced the activity of JAK2-STAT5 pathway and the proliferation of Ba/F3 and MV4-11 cells. Further study showed that JAK2 R867Q mutation promoted the expression of proliferation marker and inhibited the differentiation marker of Ba/F3 and MV4-11 cells. Thus our studies provide clues in understanding the pathogenesis of JAK2 R867Q mutation in AL. (C) 2019 Elsevier B.V. All rights reserved.