突变
调解人
癌症研究
体细胞
造血
信号转导
白血病
Janus激酶2
生物
种系突变
B细胞
免疫系统
细胞生物学
免疫学
遗传学
基因
干细胞
抗体
作者
Qingyun Wu,Hua-Yan Guo,Feng Li,Zhenyu Li,Lingyu Zeng,Kailin Xu
标识
DOI:10.3109/10428194.2013.781171
摘要
Janus kinase 2 (JAK2) is an important mediator of cytokine receptor signaling and plays key roles in hematopoietic and immune responses. The acquired JAK2 R683G(S) somatic mutations are detected in 15% of patients with B-cell acute lymphoblastic leukemia (B-ALL) and are presumed to be a biomarker for B-ALL. However, how JAK2 R683G(S) mutations lead to B-ALL is still unclear. Our results indicated that the E627 and R683 interaction played a vital role in JAK2 autoinhibition. Mutations (R683S, R683G and E627A) disrupting this interaction led to JAK2 constitutive activation, while mutations (R683K, E627D) restoring this interaction decreased its activity. Furthermore, spectroscopy experiments implied that disruption of the E627 and R683 interaction abolished JH1/JH2 domain interactions and forced the JH1 domain into the open, active conformation. Mutations abolishing this interaction promoted the proliferation of Ba/F3 cells. The results herein may provide clues to understanding the mechanism of JAK2 R683G(S) mutation-associated B-ALL.
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