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Molecular basis of JAK2 H608Y and H608N mutations in the pathology of acute myeloid leukemia.
- Source :
-
International journal of biological macromolecules [Int J Biol Macromol] 2023 Feb 28; Vol. 229, pp. 247-259. Date of Electronic Publication: 2022 Dec 15. - Publication Year :
- 2023
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Abstract
- Risk-stratification of acute myeloid leukemia (AML) based on (cyto)genetic aberrations, including hotspot mutations, deletions and point mutations have evolved substantially in recent years. With the development of next-generation sequence technology, more and more novel mutations in the AML were identified. Thus, to unravel roles and mechanism of novel mutations would improve prognostic and predictive abilities. In this study, two novel germline JAK2 His608Tyr (H608Y) and His608Asn (H608N) mutations were identified and the molecular basis of these mutations in the leukemiagenesis of AML was elucidated. Our results indicated that JAK2 H608Y and H608N mutations disrupted the hydrogen bond between Q656 and H608 which reduced the JH2 domain's activity and abolished interactions between JH1 and JH2 domains, forced JAK2 into the active conformation, facilitated the entrance of substrates and thus caused JAK2 hyperactivation. Further studies suggested that JAK2 H608Y and H608N mutations enhanced the cell proliferation and inhibited the differentiation of Ba/F3 and MV4-11 cells via activating the JAK2-STAT5 signaling pathway. Moreover, rescue experiments demonstrated that mutations repaired the hydrogen bond between Q656 and H608 displayed opposite results. Thus, this study revealed the molecular basis of JAK2 H608Y and H608N mutations in the pathology of AML.<br />Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br /> (Copyright © 2022. Published by Elsevier B.V.)
Details
- Language :
- English
- ISSN :
- 1879-0003
- Volume :
- 229
- Database :
- MEDLINE
- Journal :
- International journal of biological macromolecules
- Publication Type :
- Academic Journal
- Accession number :
- 36529225
- Full Text :
- https://doi.org/10.1016/j.ijbiomac.2022.12.121