PP2A modulation overcomes multidrug resistance in chronic lymphocytic leukemia via mPTP-dependent apoptosis.

Autor:	Jayappa KD; Department of Microbiology, Immunology, and Cancer Biology, University of Virginia (UVA) School of Medicine, Charlottesville, Virginia, USA.; Beirne B. Carter Center for Immunology Research, Charlottesville, Virginia, USA.; Department of Pharmacology, Charlottesville, Virginia, USA., Tran B; Division of Genetic Medicine, Department of Internal Medicine, the University of Michigan, Ann Arbor, Michigan, USA., Gordon VL; Department of Microbiology, Immunology, and Cancer Biology, University of Virginia (UVA) School of Medicine, Charlottesville, Virginia, USA.; Beirne B. Carter Center for Immunology Research, Charlottesville, Virginia, USA., Morris C; Department of Microbiology, Immunology, and Cancer Biology, University of Virginia (UVA) School of Medicine, Charlottesville, Virginia, USA.; Beirne B. Carter Center for Immunology Research, Charlottesville, Virginia, USA., Saha S; Department of Biochemistry and Molecular Genetics, Charlottesville, Virginia, USA., Farrington CC; Division of Genetic Medicine, Department of Internal Medicine, the University of Michigan, Ann Arbor, Michigan, USA., O'Connor CM; Division of Genetic Medicine, Department of Internal Medicine, the University of Michigan, Ann Arbor, Michigan, USA., Zawacki KP; Division of Genetic Medicine, Department of Internal Medicine, the University of Michigan, Ann Arbor, Michigan, USA., Isaac KM; Division of Hematology/Oncology, UVA School of Medicine, Charlottesville, Virginia, USA., Kester M; Department of Pharmacology, Charlottesville, Virginia, USA.; Department of Biomedical Engineering, UVA, Charlottesville, Virginia, USA., Bender TP; Department of Microbiology, Immunology, and Cancer Biology, University of Virginia (UVA) School of Medicine, Charlottesville, Virginia, USA.; Beirne B. Carter Center for Immunology Research, Charlottesville, Virginia, USA., Williams ME; Division of Hematology/Oncology, UVA School of Medicine, Charlottesville, Virginia, USA.; Cancer Center, UVA, Charlottesville, Virginia, USA., Portell CA; Division of Hematology/Oncology, UVA School of Medicine, Charlottesville, Virginia, USA.; Cancer Center, UVA, Charlottesville, Virginia, USA., Weber MJ; Department of Microbiology, Immunology, and Cancer Biology, University of Virginia (UVA) School of Medicine, Charlottesville, Virginia, USA.; Beirne B. Carter Center for Immunology Research, Charlottesville, Virginia, USA.; Cancer Center, UVA, Charlottesville, Virginia, USA., Narla G; Division of Genetic Medicine, Department of Internal Medicine, the University of Michigan, Ann Arbor, Michigan, USA.
Jazyk:	angličtina
Zdroj:	The Journal of clinical investigation [J Clin Invest] 2023 Jul 03; Vol. 133 (13). Date of Electronic Publication: 2023 Jul 03.
DOI:	10.1172/JCI155938
Abstrakt:	Targeted therapies such as venetoclax (VEN) (Bcl-2 inhibitor) have revolutionized the treatment of chronic lymphocytic leukemia (CLL). We previously reported that persister CLL cells in treated patients overexpress multiple antiapoptotic proteins and display resistance to proapoptotic agents. Here, we demonstrated that multidrug-resistant CLL cells in vivo exhibited apoptosis restriction at a pre-mitochondrial level due to insufficient activation of the Bax and Bak (Bax/Bak) proteins. Co-immunoprecipitation analyses with selective BH domain antagonists revealed that the pleiotropic proapoptotic protein (Bim) was prevented from activating Bax/Bak by "switching" interactions to other upregulated antiapoptotic proteins (Mcl-1, Bcl-xL, Bcl-2). Hence, treatments that bypass Bax/Bak restriction are required to deplete these resistant cells in patients. Protein phosphatase 2A (PP2A) contributes to oncogenesis and treatment resistance. We observed that small-molecule activator of PP2A (SMAP) induced cytotoxicity in multiple cancer cell lines and CLL samples, including multidrug-resistant leukemia and lymphoma cells. The SMAP (DT-061) activated apoptosis in multidrug-resistant CLL cells through induction of mitochondrial permeability transition pores, independent of Bax/Bak. DT-061 inhibited the growth of wild-type and Bax/Bak double-knockout, multidrug-resistant CLL cells in a xenograft mouse model. Collectively, we discovered multidrug-resistant CLL cells in patients and validated a pharmacologically tractable pathway to deplete this reservoir.
Databáze:	MEDLINE
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