Počet záznamů: 1
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 0554659 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, Dana (BTO-N) RID, ORCID
Kelemen, Cristina D. (BTO-N) RID, ORCID
Helman, K. (CZ)
Jaksa, R. (CZ)
Havranek, O. (CZ)
Anděra, Ladislav (BTO-N) ORCID, 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. Jazyk dok. eng - angličtina Země vyd. US - Spojené státy americké Klíč. slova gene-expression ; elderly-patients ; bcl-2 family ; venetoclax ; chemotherapy Vědní obor RIV FD - Onkologie a hematologie Obor OECD Oncology CEP GA19-08772S GA ČR - Grantová agentura ČR NU21-03-00386 GA MZd - Ministerstvo zdravotnictví Způsob publikování Open access Institucionální podpora BTO-N - RVO:86652036 UT WOS 000754061700001 EID SCOPUS 85122963982 DOI https://doi.org/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 Biotechnologický ústav Kontakt Monika Kopřivová, Monika.Koprivova@ibt.cas.cz, Tel.: 325 873 700 Rok sběru 2023 Elektronická adresa https://aacrjournals.org/mct/article/21/1/89/675161/Anti-apoptotic-MCL1-Protein-Represents-Critical
Počet záznamů: 1