TY - JOUR
T1 - Targeting mitochondrial respiration and the BCL2 family in high-grade MYC-associated B-cell lymphoma
AU - Donati, Giulio
AU - Ravà, Micol
AU - Filipuzzi, Marco
AU - Nicoli, Paola
AU - Cassina, Laura
AU - Verrecchia, Alessandro
AU - Doni, Mirko
AU - Rodighiero, Simona
AU - Parodi, Federica
AU - Boletta, Alessandra
AU - Vellano, Christopher P.
AU - Marszalek, Joseph R.
AU - Draetta, Giulio F.
AU - Amati, Bruno
N1 - Publisher Copyright:
© 2021 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies
PY - 2022/3
Y1 - 2022/3
N2 - 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.
AB - 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.
KW - BCL2
KW - DLBCL
KW - Integrated Stress Response
KW - MYC
KW - OxPhos
KW - chemotherapy
UR - http://www.scopus.com/inward/record.url?scp=85118856817&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85118856817&partnerID=8YFLogxK
U2 - 10.1002/1878-0261.13115
DO - 10.1002/1878-0261.13115
M3 - Article
C2 - 34632715
AN - SCOPUS:85118856817
SN - 1574-7891
VL - 16
SP - 1132
EP - 1152
JO - Molecular oncology
JF - Molecular oncology
IS - 5
ER -