Targeting cytohesin-l suppresses acute myeloid leukemia progression and overcomes resistance to ABT-199  

作　　者：Wen-xiang Ren Hao Guo Sheng-yan Lin Si-yi Chen Yao-ying Long Liu-yue Xu Di Wu Yu-lin Cao Jiao Qu Bian-lei Yang Hong-pei Xu He Li Ya-li Yu An-yuan Zhang Shan Wang Yi-cheng Zhang Ke-shu Zhou Zhi-chao Chen Qiu-bai Li 

机构地区：[1]Department of Hematology,Union Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430022,China [2]Department of Hematology,Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430022,China [3]Department of Hematology,The Affliated Cancer Hospital of Zhengzhou University&Henan Cancer Hospital,Zhengzhou 45ooo,China [4]Department of Rheumatology and Immunology,Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430030,China [5]Department of Rheumatology and Immunology,Union Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430022,China [6]Hubei Engineering Research Center for Application of Extracelular Vesicles,Hubei University of Science and Technology,Xianning 437100,China

出　　处：《Acta Pharmacologica Sinica》2024年第1期180-192,共13页中国药理学报（英文版）

基　　金：supported by grants from the National Natural Science Foundation of China(81974221,81974009,81470330,and 81272624);the Natural Science Foundation of Henan(232300421280).

摘　　要：Adhesion molecules play essential roles in the homeostatic regulation and malignant transformation of hematopoietic cells.The dysregulated expression of adhesion molecules in leukemic cells accelerates disease progression and the development of drug resistance.Thus,targeting adhesion molecules represents an attractive anti-leukemic therapeutic strategy.In this study,we investigated the prognostic role and functional significance of cytohesin-1(CYTH1)in acute myeloid leukemia(AML).Analysis of AML patient data from the GEPIA and BloodSpot databases revealed that CYTH1 was significantly overexpressed in AML and independently correlated with prognosis.Functional assays using AML cell lines and an AML xenograft mouse model confrmed that CYTH1 depletion significantly inhibited the adhesion,migration,homing,and engraftment of leukemic cells,delaying disease progression and prolonging animal survival.The CYTH1 inhibitor SecinH3 exerted in vitro and in vivo anti-leukemic effects by disrupting leukemic adhesion and survival programs.In line with the CYTH1 knockdown results,targeting CYTH1 by SecinH3 suppressed integrin-associated adhesion signaling by reducing ITGB2 expression.SecinH3 treatment efficiently induced the apoptosis and inhibited the growth of a panel of AML cell lines(MOLM-13,MV4-11 and THP-1)with mixed-lineage leukemia gene rearrangement,partly by reducing the expression of the anti-apoptotic protein MCL1.Moreover,we showed that SecinH3 synergized with the BCL2-selective inhibitor ABT-199(venetoclax)to inhibit the proliferation and promote the apoptosis of ABT-199-resistant leukemic cells.Taken together,our results not only shed light on the role of CYTH1 in cell-adhesion-mediated leukemogenesis but also propose a novel combination treatment strategyfor AML.

关 键 词：acute myeloid leukemia CYTH1 cell adhesion SecinH3 MCL1 ABT-199 

分 类 号：R733.71[医药卫生—肿瘤]