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 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.

Automated summary

MYC activity is closely correlated with gene expression signatures related to oxidative phosphorylation in DLBCL, sensitizing B cells to the ETC complex I inhibitor IACS-010759. The combination of BCL2 inhibitor venetoclax and IACS-010759 showed synergy in DHL with concurrent activation of MYC and BCL2, while in BCL2-negative lymphoma cells, the Mcl-1 inhibitor S63845 potentiated killing by IACS-010759. This suggests a novel therapeutic approach against aggressive, MYC-associated DLBCL variants.