Roles of T875N somatic mutation in the activity, structural stability of JAK2 and the transformation of OCI-AML3 cells
Roles of T875N somatic mutation in the activity, structural stability of JAK2 and the transformation of OCI-AML3 cells
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T875N体细胞突变在JAK2活性、结构稳定性和OCI-AML3细胞转化中的作用
DOI：
10.1016/j.ijbiomac.2019.07.065
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发表时间：
2019-09-15
影响因子：
8.2
通讯作者：
Wu, Qing-Yun
中科院分区：
文献类型：
--
作者：
Chen, Chong;Li, Feng;Wu, Qing-Yun
JAK 2中的激活突变已经在患有各种血液恶性肿瘤的患者中描述，包括急性髓性白血病（AML）和骨髓增生性肿瘤。然而，这些突变在JAK 2活性、结构稳定性和AML病理学中的机制仍然知之甚少。JAK 2 T875 N体细胞突变已在约5.2%的AML患者中检测到。但JAK 2 T875 N突变在AML发病中的结构基础和机制尚不清楚。结果表明，JAK 2的T875 N突变破坏了T875和D873的相互作用，破坏了JH 1结构域的紧密结构，迫使其进入活性构象，促进底物进入，从而导致JAK 2的超活化。突变（T875 N、T875 A、D873 A和D873 G）破坏了T875和D873的相互作用，增强了JAK 2的活性，降低了其结构稳定性和JH 2结构域的活性，进一步增强了JAK 2的活性，而突变（T875 R、D873 E、T875 R/D873 E）修复了这种相互作用，表现出相反的结果。JAK 2 T875 N突变增强了JAK 2-STAT 5通路的活性，促进了OCI-AML 3细胞的增殖和转化。本研究为了解T875 N突变导致JAK 2过度激活的结构基础及其在AML病理中的作用提供了线索。(C)2019 Elsevier B. V.版权所有。
Activating mutations in JAK2 have been described in patients with various hematologic malignancies including acute myeloid leukemia (AML) and myeloproliferative neoplasms. However, mechanism of these mutations in JAK2's activity, structural stability and pathology of AML remains poorly understood. The JAK2 T875N somatic mutation has been detected in about 5.2% of AML patients. But the structural basis and mechanism of JAK2 T875N mutation in the pathology of AML is still unclear. Our results suggested that JAK2 T875N mutation disrupted the T875 and D873 interaction which destroyed the compact structure of JH1 domain, forced it into the active conformation, facilitated the entrance of substrate and thus led to JAK2 hyperactivation. Mutations (T875N, T875A, D873A and D873G) disrupted the T875 and D873 interaction enhanced JAK2's activity, decreased its structural stability and JH2 domain's activity which further enhanced JAK2's activity, while mutations (T875R, D873E, T875R/D873E) repaired this interaction displayed opposite results. Moreover, JAK2 T875N mutation enhanced the activity of JAK2-STAT5 pathway, promoted the proliferation and transformation of OCI-AML3 cells. This study provides clues in understanding structural basis of T875N mutation caused JAK2 hyperactivation and its roles in the pathology of AML. (C) 2019 Elsevier B.V. All rights reserved.