دورية أكاديمية
أعرض في EDS

Targeting cytohesin-1 suppresses acute myeloid leukemia progression and overcomes resistance to ABT-199.

التفاصيل البيبلوغرافية
العنوان: Targeting cytohesin-1 suppresses acute myeloid leukemia progression and overcomes resistance to ABT-199.
المؤلفون: Ren WX; Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China., Guo H; Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.; Department of Hematology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450000, China., Lin SY; Department of Rheumatology and Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China., Chen SY; Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China., Long YY; Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China., Xu LY; Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China., Wu D; Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China., Cao YL; Department of Rheumatology and Immunology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China., Qu J; Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China., Yang BL; Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China., Xu HP; Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China., Li H; Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China., Yu YL; Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China., Zhang AY; Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China., Wang S; Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China., Zhang YC; Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China., Zhou KS; Department of Hematology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450000, China. drzhouks77@163.com., Chen ZC; Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. chenzhichao@hust.edu.cn., Li QB; Department of Rheumatology and Immunology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. qiubaili@hust.edu.cn.; Hubei Engineering Research Center for Application of Extracellular Vesicles, Hubei University of Science and Technology, Xianning, 437100, China. qiubaili@hust.edu.cn.
المصدر: Acta pharmacologica Sinica [Acta Pharmacol Sin] 2024 Jan; Vol. 45 (1), pp. 180-192. Date of Electronic Publication: 2023 Aug 29.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Nature Publishing Group Country of Publication: United States NLM ID: 100956087 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1745-7254 (Electronic) Linking ISSN: 16714083 NLM ISO Abbreviation: Acta Pharmacol Sin Subsets: MEDLINE
أسماء مطبوعة: Publication: 2009- : New York : Nature Publishing Group
Original Publication: Beijing, China : Science Press, c2000-
مواضيع طبية MeSH: Leukemia, Myeloid, Acute*/drug therapy , Antineoplastic Agents*/pharmacology , Antineoplastic Agents*/therapeutic use, Humans ; Mice ; Animals ; Sulfonamides/pharmacology ; Sulfonamides/therapeutic use ; Apoptosis ; Cell Adhesion Molecules ; Disease Progression ; Cell Line, Tumor
مستخلص: 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 confirmed 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 strategy for AML.
(© 2023. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)
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فهرسة مساهمة: Keywords: ABT-199; CYTH1; MCL1; SecinH3; acute myeloid leukemia; cell adhesion
المشرفين على المادة: N54AIC43PW (venetoclax)
0 (cytohesin-1)
0 (Sulfonamides)
0 (Antineoplastic Agents)
0 (Cell Adhesion Molecules)
تواريخ الأحداث: Date Created: 20230829 Date Completed: 20240108 Latest Revision: 20240108
رمز التحديث: 20240108
مُعرف محوري في PubMed: PMC10770340
DOI: 10.1038/s41401-023-01142-2
PMID: 37644132
قاعدة البيانات: MEDLINE
الوصف
تدمد:1745-7254
DOI:10.1038/s41401-023-01142-2