Anti-apoptotic MCL1 Protein Represents Critical Survival Molecule for Most Burkitt Lymphomas and BCL2-negative Diffuse Large B-cell Lymphomas

0557905 - ÚMG 2023 RIV US eng J - Journal Article
Klánová, M. - Kazantsev, D. - Pokorná, E. - Zikmund, T. - Karolová, J. - Behounek, M. - Renesova, N. - Sovilj, D. - Kelemen, C. - Helman, K. - Jaksa, R. - Havránek, O. - Anděra, Ladislav - Trněný, M. - Klener, P.
Anti-apoptotic MCL1 Protein Represents Critical Survival Molecule for Most Burkitt Lymphomas and BCL2-negative Diffuse Large B-cell Lymphomas.
Molecular Cancer Therapeutics. Roč. 21, č. 1 (2022), s. 89-99. ISSN 1535-7163. E-ISSN 1538-8514
Institutional support: RVO:68378050
Keywords : gene-expression * elderly-patients * bcl-2 family * venetoclax * chemotherapy * inhibition * mutations * subgroups * abt-199 * dlbcl
OECD category: Oncology
Impact factor: 5.7, year: 2022
Method of publishing: Open access
https://aacrjournals.org/mct/article/21/1/89/675161/Anti-apoptotic-MCL1-Protein-Represents-Critical

The pro-survival MCL1 protein is overexpressed in many S63845 is a highly specific inhibitor of MCL1. We analyzed models of diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma. Annexin V-based cytotoxic assays, Western blot analysis, protein co-immunoprecipitation, and cell clones with manipulated expression of BCL2 family proteins were used to analyze mechanisms of sensitivity to S63845. Experimental in vivo therapy with S63845 and/or venetoclax was performed using patient-derived xenografts (PDX) of treatment-refractory B-NHL. A subset of DLBCL and majority of Burkitt lymphoma cell lines were sensitive to S63845. The level of BCL2 protein expression was the major determinant of resistance to S63845: BCL2 serves as a buffer for pro-apoptotic proteins released from MCL1 upon exposure to S63845. While BCL2-negative lympho-mas were effectively eliminated by single-agent S63845, its combination with venetoclax was synthetically lethal in BCL2-positive PDX models. Concerning MCL1, both, the level of MCL1 protein expression, and its occupational status represent key factors mediating sensitivity to S63845. In contrast to MCL1-BIM/BAK1 complexes that prime lymphoma cells for S63845-mediated apoptosis, MCL1-NOXA complexes are associated with S63845 resistance. In conclusion, MCL1 represents a critical survival molecule for most Burkitt lymphomas and a subset of BCL2-negative DLBCLs. The level of BCL2 and MCL1 expression and occupational status of MCL1 belong to the key modulators of sensitivity/resistance to S63845. Co-treatment with venetoclax can overcome BCL2-mediated resistance to S63845, and enhance efficacy of MCL1 inhibitors in BCL2-positive aggressive B-NHL.
Permanent Link: http://hdl.handle.net/11104/0331789