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Reciprocal interactions among Cobll1, PACSIN2, and SH3BP1 regulate drug resistance in chronic myeloid leukemia

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Title
Reciprocal interactions among Cobll1, PACSIN2, and SH3BP1 regulate drug resistance in chronic myeloid leukemia
Author(s)
Park, Kibeom; Yoo, Hee-Seop; Chang-Kyu Oh; Lee, Joo Rak; Chung, Hee Jin; Kim, Ha-Neul; Kim, Soo-Hyun; Kee, Kyung-Mi; Kim, Tong Yoon; Kim, Myungshin; Byung-Gyu Kim; Jae Sun Ra; Kyungjae Myung; Hongtae Kim; Han, Seung Hun; Seo, Min-Duk; Yoonsung Lee; Kim, Dong-Wook
Publication Date
2022-11
Journal
Cancer Medicine, v.11, no.212, pp.4005 - 4020
Publisher
John Wiley and Sons Inc
Abstract
© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.Cobll1 affects blast crisis (BC) progression and tyrosine kinase inhibitor (TKI) resistance in chronic myeloid leukemia (CML). PACSIN2, a novel Cobll1 binding protein, activates TKI-induced apoptosis in K562 cells, and this activation is suppressed by Cobll1 through the interaction between PACSIN2 and Cobll1. PACSIN2 also binds and inhibits SH3BP1 which activates the downstream Rac1 pathway and induces TKI resistance. PACSIN2 competitively interacts with Cobll1 or SH3BP1 with a higher affinity for Cobll1. Cobll1 preferentially binds to PACSIN2, releasing SH3BP1 to promote the SH3BP1/Rac1 pathway and suppress TKI-mediated apoptosis and eventually leading to TKI resistance. Similar interactions among Cobll1, PACSIN2, and SH3BP1 control hematopoiesis during vertebrate embryogenesis. Clinical analysis showed that most patients with CML have Cobll1 and SH3BP1 expression at the BC phase and BC patients with Cobll1 and SH3BP1 expression showed severe progression with a higher blast percentage than those without any Cobll1, PACSIN2, or SH3BP1 expression. Our study details the molecular mechanism of the Cobll1/PACSIN2/SH3BP1 pathway in regulating drug resistance and BC progression in CML.
URI
https://pr.ibs.re.kr/handle/8788114/12820
DOI
10.1002/cam4.4727
ISSN
2045-7634
Appears in Collections:
Center for Genomic Integrity(유전체 항상성 연구단) > 1. Journal Papers (저널논문)
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