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

I. Baccelli, Y. Gareau, B. Lehnertz, S. Gingras, J.-F. Spinella, A. Beautrait, S. Corneau, N. Mayotte, I. Boivin, S. Girard, T. MacRae, M. Frechette, K. Leveille, J. Krosl, C. Thiollier, V. Lavallee, E. Kanshin, T. Bertomeu, J. Coulombe-Huntington, C. St-Denis, M.-E. Bordeleau, G. Boucher, P. P. Roux, S. Lemieux, M. Tyers, , G. Sauvageau

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Abstract

Inhibition of oxidative phosphorylation (OXPHOS) is a promising therapeutic strategy in Acute Myeloid Leukemia (AML), but patients respond heterogeneously. Through chemically interrogation of 200 sequenced specimens, we identified Mubritinib as a strong in vitro and in vivo anti-leukemic compound, acting through ubiquinone-dependent inhibition of Electron Transport Chain complex I (ETC1). ETC1 targeting showed selective toxicity against a subgroup of chemotherapy-resistant leukemias exhibiting OXPHOS hyperactivity, high expression of mitochondrial activity-related genes, and mutations affecting NPM1, FLT3 and DNMT3A. Altogether, our work thus identifies a novel ETC1 inhibitor with high clinical potential and reveals the landscape of OXPHOS dependency in AML.

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