Abstract A87: Targeting the mitochondrial quality control machinery in acute myeloid leukemia

Abstract

Abstract Recently, we demonstrated that a subset of AML cells and stem cells have metabolic vulnerabilities in the mitochondria and oxidative phosphorylation (OXPHOS) chain that could impact on the ability of AML and AML stem cells to handle increased electron flux in the respiratory chain (Sriskanthadevan et al., Blood, 2015). To identify additional vulnerabilities in the mitochondria of AML cells and AML stem cells, we analyzed RNA expression levels of a panel of mitochondrial quality control proteins using the nCounter Analysis System (Nanostring technologies) in bulk as well as the progenitor enriched fraction of AML patients and normal donors. Among the top hits was the mitochondrial processing peptidase (MPP) that was upregulated in AML cells and progenitors compared to normal hematopoietic cells. MPP is a metallopeptidase composed of a regulatoryα subunit and a proteolytic β subunit that cleaves presequences from several nuclear encoded and mitochondrially imported proteins. To further analyze the expression of MPP in AML, we analyzed publicly available datasets (Eppert et al., (GSE30377), Laurenti et al., (GSE42414) and Norversthen et al., (GSE24759)). GSEA (Gene Set Enrichment Analysis) on stem enriched as well as bulk AML cells demonstrated upregulation of MPPα and β as well as increased expression of the mitochondrial protein import pathway in a subset of AML cells and stem cells compared to normal hematopoietic cells and stem cells. To understand the importance of MPP in AML cells, we knocked down MPPα and β using shRNA in lentiviral vectors and confirmed target knockdown by immunoblotting. Knockdown of MPPα or β reduced the growth and viability of OCI-AML2 cells. Mechanistically, knockdown of MPP β increased mitochondrial ROS generation. Thus, the mitochondrial protein import pathway is upregulated in a subset of AML cells and stem cells. Moreover inhibition of this pathway at the level of MPPα and β is cytotoxic to AML cells and disrupts mitochondrial function. Citation Format: Danny V. Jeyaraju, Veronique Voisin, Ashwin Ramakrishnan, Rose Hurren, Neil Maclean, Marcela Gronda, Mark Minden, Gary Bader, Aaron D. Schimmer. Targeting the mitochondrial quality control machinery in acute myeloid leukemia. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr A87.