GSE130906
Mubritinib Targets the Electron Transport Chain Complex I and Reveals the Landscape of OXPHOS Dependency in Acute Myeloid Leukemia
To identify novel therapeutic targets in Acute Myeloid Leukemia (AML), we chemically interrogated 200 sequenced primary specimens. We identified Mubritinib, a known ERBB2 inhibitor, as a strong in vitro and in vivo anti-leukemic compound. We demonstrate that, in the context of AML, Mubritinib functions through ubiquinone-dependent inhibition of Electron Transport Chain (ETC) complex I activity. Resistance to Mubritinib characterized normal CD34+ hematopoietic cells and chemotherapy-sensitive AMLs, which displayed transcriptomic hallmarks of hypoxia. Conversely, sensitivity correlated with mitochondrial function-related gene expression levels and characterized a large subset of chemotherapy-resistant AMLs with oxidative phosphorylation (OXPHOS) hyperactivity. Altogether, our work thus identifies a novel ETC complex I inhibitor and reveals for the first time the genetic landscape of OXPHOS dependency in this disease. Overall design: Nalm-6 cells infected with the EKO sgRNA library (Bertomeu et al. 2017, PMID:29038160), after 7 days of Cas9 induction with doxycycline, were exposed to either 200nM mubritinib or 0.1% DMSO for 8 days. sgRNA abundance was then assessed by high-throughput sequencing. Cells collected before the treatment and DMSO-treated cells served as controls.