Targeting mitochondrial respiration and the BCL2 family in high‐grade MYC‐associated B‐cell lymphoma

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...

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Published in:Molecular oncology Vol. 16; no. 5; pp. 1132 - 1152
Main Authors: Donati, Giulio, Ravà, Micol, Filipuzzi, Marco, Nicoli, Paola, Cassina, Laura, Verrecchia, Alessandro, Doni, Mirko, Rodighiero, Simona, Parodi, Federica, Boletta, Alessandra, Vellano, Christopher P., Marszalek, Joseph R., Draetta, Giulio F., Amati, Bruno
Format: Journal Article
Language:English
Published: United States John Wiley & Sons, Inc 01.03.2022
John Wiley and Sons Inc
Wiley
Subjects:
Apoptosis
B-cell lymphoma
BCL2
Chemotherapy
DLBCL
Drug development
Electron transport chain
Gene expression
Glucose
Humans
Integrated Stress Response
Leukemia
Lymphocytes B
Lymphoma
Lymphoma, Large B-Cell, Diffuse - drug therapy
Lymphoma, Large B-Cell, Diffuse - genetics
Malignancy
Medical prognosis
Mitochondria
MYC
Myc protein
Oncogenes
Oxidative phosphorylation
OxPhos
Patients
Phosphorylation
Proto-Oncogene Proteins c-bcl-2 - metabolism
Proto-Oncogene Proteins c-myc - genetics
Proto-Oncogene Proteins c-myc - metabolism
Respiration
Therapeutic targets
Transcription factors
Transplants & implants
United States > US
Italy
Germany
BCL2
DLBCL
Integrated Stress Response
OxPhos
chemotherapy
MYC
ISSN:1574-7891, 1878-0261, 1878-0261
Online Access:Get full text
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Summary: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. We show that MYC activity is closely correlated with OxPhos‐associated gene signatures in human B‐cell lymphomas and sensitizes B cells to the mitochondrial complex I inhibitor IACS‐010759. This molecule shows synergy with select BH3‐mimetic drugs in killing cancer cells, and in particular with the BCL2 inhibitor venetoclax against the aggressive double‐hit lymphoma subtype, with promising antitumoral effects in preclinical models.
Bibliography:Giulio Donati and Micol Ravà contributed equally to this article
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ISSN:1574-7891
1878-0261
1878-0261
DOI:10.1002/1878-0261.13115