Anti-apoptotic MCL1 Protein Represents Critical Survival Molecule for Most Burkitt Lymphomas and BCL2-negative Diffuse Large B-cell Lymphomas
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68378050%3A_____%2F22%3A00557905" target="_blank" >RIV/68378050:_____/22:00557905 - isvavai.cz</a>
Alternative codes found
RIV/86652036:_____/22:00554659 RIV/00216208:11110/22:10439498 RIV/00064165:_____/22:10439498 RIV/61384399:31140/22:00057637
Result on the web
<a href="https://aacrjournals.org/mct/article/21/1/89/675161/Anti-apoptotic-MCL1-Protein-Represents-Critical" target="_blank" >https://aacrjournals.org/mct/article/21/1/89/675161/Anti-apoptotic-MCL1-Protein-Represents-Critical</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1158/1535-7163.MCT-21-0511" target="_blank" >10.1158/1535-7163.MCT-21-0511</a>
Alternative languages
Result language
angličtina
Original language name
Anti-apoptotic MCL1 Protein Represents Critical Survival Molecule for Most Burkitt Lymphomas and BCL2-negative Diffuse Large B-cell Lymphomas
Original language description
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.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
30204 - Oncology
Result continuities
Project
Result was created during the realization of more than one project. More information in the Projects tab.
Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2022
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Molecular Cancer Therapeutics
ISSN
1535-7163
e-ISSN
1538-8514
Volume of the periodical
21
Issue of the periodical within the volume
1
Country of publishing house
US - UNITED STATES
Number of pages
11
Pages from-to
89-99
UT code for WoS article
000754061700001
EID of the result in the Scopus database
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