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

Irène Baccelli; Yves Gareau; Bernhard Lehnertz; Stéphane Gingras; Jean-François Spinella; Alexandre Beautrait; Sophie Corneau; Nadine Mayotte; Isabel Boivin; Simon Girard; Tara MacRae; Mélanie Frechette; Koryne Leveillé; Jana Krosl; Clarisse Thiollier; Vincent-Philippe Lavallée; Evgeny Kanshin; Thierry Bertomeu; Jasmin Coulombe-Huntington; Corinne St-Denis; Marie-Eve Bordeleau; Geneviève Boucher; Philippe P. Roux; Sébastien Lemieux; Mike Tyers; Pierre Thibault; Josée Hébert; Anne Marinier; Guy Sauvageau

doi:10.1101/513887

Cancer BiologybioRxivJan 15, 2019

Preprint

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

Irène Baccelli, Yves Gareau, Bernhard Lehnertz iD, Stéphane Gingras, Jean-François Spinella iD, Alexandre Beautrait, Sophie Corneau iD, Nadine Mayotte iD, Isabel Boivin iD, Simon Girard, Tara MacRae iD, Mélanie Frechette, Koryne Leveillé, Jana Krosl, Clarisse Thiollier, Vincent-Philippe Lavallée, Evgeny Kanshin, Thierry Bertomeu iD, Jasmin Coulombe-Huntington, Corinne St-Denis, Marie-Eve Bordeleau, Geneviève Boucher iD, Philippe P. Roux iD, Sébastien Lemieux iD, Mike Tyers iD, , Guy Sauvageau iD

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.

PDF DOI