Faculty, Staff and Student Publications
Targeting Mitochondrial Respiration and the BCL2 Family in High-Grade MYC-Associated B-Cell Lymphoma
Publication Date
3-1-2022
Journal
Molecular Oncology
Abstract
Multiple molecular features, such as activation of specific oncogenes (e.g., MYC, BCL2) or a variety of gene expression signatures, have been associated with disease course in diffuse large B-cell lymphoma (DLBCL), although their relationships and implications for targeted therapy remain to be fully unraveled. We report that MYC activity is closely correlated with-and most likely a driver of-gene signatures related to oxidative phosphorylation (OxPhos) in DLBCL, pointing to OxPhos enzymes, in particular mitochondrial electron transport chain (ETC) complexes, as possible therapeutic targets in high-grade MYC-associated lymphomas. In our experiments, indeed, MYC sensitized B cells to the ETC complex I inhibitor IACS-010759. Mechanistically, IACS-010759 triggered the integrated stress response (ISR) pathway, driven by the transcription factors ATF4 and CHOP, which engaged the intrinsic apoptosis pathway and lowered the apoptotic threshold in MYC-overexpressing cells. In line with these findings, the BCL2-inhibitory compound venetoclax synergized with IACS-010759 against double-hit lymphoma (DHL), a high-grade malignancy with concurrent activation of MYC and BCL2. In BCL2-negative lymphoma cells, instead, killing by IACS-010759 was potentiated by the Mcl-1 inhibitor S63845. Thus, combining an OxPhos inhibitor with select BH3-mimetic drugs provides a novel therapeutic principle against aggressive, MYC-associated DLBCL variants.
Keywords
Humans, Lymphoma, Large B-Cell, Diffuse, Oncogenes, Proto-Oncogene Proteins c-bcl-2, Proto-Oncogene Proteins c-myc, Respiration, BCL2, chemotherapy, DLBCL, Integrated Stress Response, MYC, OxPhos
DOI
10.1002/1878-0261.13115
PMID
34632715
PMCID
PMC8895457
PubMedCentral® Posted Date
11-11-2021
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
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Bioinformatics Commons, Biomedical Informatics Commons, Genetic Phenomena Commons, Medical Genetics Commons, Oncology Commons