Targeting ERR[alpha] promotes cytotoxic effects against acute myeloid leukemia through suppressing mitochondrial oxidative phosphorylation

Acute myeloid leukemia (AML) is an aggressive blood cancer with poor clinical outcomes. Emerging data suggest that mitochondrial oxidative phosphorylation (mtOXPHOS) plays a significant role in AML tumorigenesis, progression, and resistance to chemotherapies. However, how the mtOXPHOS is regulated in AML cells is not well understood. In this study, we investigated the oncogenic functions of ERR[alpha] in AML by combining in silico, in vitro, and in vivo analyses and showed ERR[alpha] is a key regulator of mtOXPHOS in AML cells. The increased ERR[alpha] level was associated with worse clinical outcomes of AML patients. Single cell RNA-Seq analysis of human primary AML cells indicated that ERR[alpha]-expressing cancer cells had significantly higher mtOXPHOS enrichment scores. Blockade of ERR[alpha] by pharmacologic inhibitor (XCT-790) or gene silencing suppressed mtOXPHOS and increased anti-leukemic effects in vitro and in xenograft mouse models. Keywords: AML, ERR[alpha], Mitochondrial oxidative phosphorylation, Apoptosis