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Anti-apoptotic MCL1 Protein Represents Critical Survival Molecule for Most Burkitt Lymphomas and BCL2-negative Diffuse Large B-cell Lymphomas
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SYSNO ASEP 0557905 Druh ASEP J - Článek v odborném periodiku Zařazení RIV J - Článek v odborném periodiku Poddruh J Článek ve WOS Název Anti-apoptotic MCL1 Protein Represents Critical Survival Molecule for Most Burkitt Lymphomas and BCL2-negative Diffuse Large B-cell Lymphomas Tvůrce(i) Klánová, M. (CZ)
Kazantsev, D. (CZ)
Pokorná, E. (CZ)
Zikmund, T. (CZ)
Karolová, J. (CZ)
Behounek, M. (CZ)
Renesova, N. (CZ)
Sovilj, D. (CZ)
Kelemen, C. (CZ)
Helman, K. (CZ)
Jaksa, R. (CZ)
Havránek, O. (CZ)
Anděra, Ladislav (UMG-J) RID
Trněný, M. (CZ)
Klener, P. (CZ)Celkový počet autorů 15 Zdroj.dok. Molecular Cancer Therapeutics. - : American Association for Cancer Research - ISSN 1535-7163
Roč. 21, č. 1 (2022), s. 89-99Poč.str. 11 s. Forma vydání Online - E Jazyk dok. eng - angličtina Země vyd. US - Spojené státy americké Klíč. slova gene-expression ; elderly-patients ; bcl-2 family ; venetoclax ; chemotherapy ; inhibition ; mutations ; subgroups ; abt-199 ; dlbcl Vědní obor RIV EB - Genetika a molekulární biologie Obor OECD Oncology Způsob publikování Open access Institucionální podpora UMG-J - RVO:68378050 UT WOS 000754061700001 DOI 10.1158/1535-7163.MCT-21-0511 Anotace 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. Pracoviště Ústav molekulární genetiky Kontakt Nikol Škňouřilová, nikol.sknourilova@img.cas.cz, Tel.: 241 063 217 Rok sběru 2023 Elektronická adresa https://aacrjournals.org/mct/article/21/1/89/675161/Anti-apoptotic-MCL1-Protein-Represents-Critical
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