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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

Qing-Yun Wu, Meng-Meng Ma, Sen Zhang, Jiang Cao, Zhi-Ling Yan, Chong Chen, Zhen-Yu Li, Ling-Yu Zeng, Xiao-Yun Wang, Feng Li, Kai-Lin Xu

Int J Biol Macromol. 2019 Sep 1;136:209-219.

PMID: 31199972

Abstract:

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 R867Q mutation 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 R867Q and 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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR42416390	Jak2 Jh1Jh2 Active human			Price

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