Genetic Landscape of Electron Transport Chain Complex I Dependency in Acute Myeloid Leukemia

Abstract

38Inhibition of oxidative phosphorylation (OXPHOS) is a promising therapeutic strategy in Acute 39 Myeloid Leukemia (AML), but patients respond heterogeneously. Through chemically 40 interrogation of 200 sequenced specimens, we identified Mubritinib as a strong in vitro and in 41 vivo anti-leukemic compound, acting through ubiquinone-dependent inhibition of Electron 42 Transport Chain complex I (ETC1). ETC1 targeting showed selective toxicity against a subgroup 43 of chemotherapy-resistant leukemias exhibiting OXPHOS hyperactivity, high expression of 44 mitochondrial activity-related genes, and mutations affecting NPM1, FLT3 and DNMT3A. 45Altogether, our work thus identifies a novel ETC1 inhibitor with high clinical potential and reveals 46 the landscape of OXPHOS dependency in AML. 47 Keywords 48 Acute Myeloid Leukemia, Metabolism, Oxidative Phosphorylation, Mitochondrial Respiration, 49 Electron Transport Chain Complex I, NADH dehydrogenase inhibitor, Precision Medicine, 50 Therapeutic Target. 51 3 Main 52 Acute Myeloid Leukemia (AML) is a highly lethal disease, with a five-year overall survival rate of 53 only 27% 1,2 . Standard treatment for AML includes a combination of cytarabine (AraC) and 54 anthracycline as an induction regimen, followed by consolidation chemotherapy or 55 hematopoietic stem cell transplantation, depending on the patient's genetic risk class 3 . this study, we interrogated 200 genetically diverse primary AML patient specimens of the well-91 characterized Leucegene cohort (www.leucegene.ca) using an unbiased chemo-genomic 92 approach. Through this process, we identified a novel ubiquinone-dependent Electron Transport 93 Chain (ETC) complex I inhibitor and uncovered the genetic landscape of OXPHOS dependency 94 in this disease. 95 96 4 Results 97 Mubritinib targets a subset of poor outcome AMLs 98The Leucegene collection of sequenced AML specimens comprises 263 de novo non-M3

Identification of Mubritinib (TAK 165) as an inhibitor of KSHV driven primary effusion lymphoma via disruption of mitochondrial OXPHOS metabolism

“…While Mubritinib was originally identified as a HER2/ErbB2 inhibitor [37], our findings suggest that its selectivity for PEL growth inhibition is dependent on its additional activity in blocking electron transport and mitochondrial metabolism [39]. Metabolic processes were recently determined to be among the top hits in a CRISPR screen for essential pathways in PEL cells [57].…”

“…Therefore, it was proposed that Mubritinib acted by a mechanism that does not involve inhibition of HER2/ ErbB2. More recently, Baccelli et al provided compelling evidence that Mubritinib selectively inhibits growth of a subset of acute myeloid leukemia (AML) cells that rely on mitochondrial oxidative phosphorylation (OXPHOS) and anaerobic glycolysis [39]. They determined that the molecular target for Mubritinib in these cells was the electron transport chain (ETC) complex I.…”

“…Given recent literature that suggests that Mubritinib can inhibit the electron transport chain (ETC) complex I [39], we next investigated whether published ETC complex I inhibitors exhibit similar selectivity for growth inhibition of PEL cells ( Figure 7A-7C, Supplementary Table 2). Rotenone, like Mubritinib, displayed clear selectivity for inhibition of PEL cell growth at nanomolar concentrations ( Figure 7B).…”

“…In AML cells, inhibition of ETC complex I by Mubritinib was accompanied by specific changes in the levels of various metabolites [39]. To assess the effect of Mubritinib on metabolites in PEL cells, we performed a global metabolomic analysis by mass spectrometry for a panel of B-cells, including KSHV + BC1 and BCBL1, and KSHV -BJAB and LCL352 ( Figure 8A).…”

A cell-based, infectious-free, platform to identify inhibitors of lassa virus ribonucleoprotein (vRNP) activity

“…Mubritinib has been recently identified as a novel mETC complex I inhibitor (Baccelli IG et al, 2019), which may have contributed to its anti-LCMV activity. Moreover, rotenone, another validated mETC complex I inhibitor (Majander et al, 1996), exhibited also a potent (EC 50 = 0.66 μM; SI > 75) anti-LCMV activity.…”