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Mubritinib Targets the Electron Transport Chain Complex I and Reveals the Landscape of OXPHOS Dependency in Acute Myeloid Leukemia.
Baccelli, Irène; Gareau, Yves; Lehnertz, Bernhard; Gingras, Stéphane; Spinella, Jean-François; Corneau, Sophie; Mayotte, Nadine; Girard, Simon; Frechette, Mélanie; Blouin-Chagnon, Valérie; Leveillé, Koryne; Boivin, Isabel; MacRae, Tara; Krosl, Jana; Thiollier, Clarisse; Lavallée, Vincent-Philippe; Kanshin, Evgeny; Bertomeu, Thierry; Coulombe-Huntington, Jasmin; St-Denis, Corinne; Bordeleau, Marie-Eve; Boucher, Geneviève; Roux, Philippe P; Lemieux, Sébastien; Tyers, Mike; Thibault, Pierre; Hébert, Josée; Marinier, Anne; Sauvageau, Guy.
Afiliación
  • Baccelli I; The Leucegene Project at Institute for Research in Immunology (IRIC) and Cancer, Université de Montréal, 2950 Chemin de Polytechnique Pavillon, Marcelle-Coutu, Montréal, QC H3T 1J4, Canada. Electronic address: baccelli@gmail.com.
  • Gareau Y; The Leucegene Project at Institute for Research in Immunology (IRIC) and Cancer, Université de Montréal, 2950 Chemin de Polytechnique Pavillon, Marcelle-Coutu, Montréal, QC H3T 1J4, Canada; Department of Chemistry, Université de Montréal Pavillon Roger-Gaudry, 2900 Boulevard Édouard-Montpetit, Montr
  • Lehnertz B; The Leucegene Project at Institute for Research in Immunology (IRIC) and Cancer, Université de Montréal, 2950 Chemin de Polytechnique Pavillon, Marcelle-Coutu, Montréal, QC H3T 1J4, Canada.
  • Gingras S; The Leucegene Project at Institute for Research in Immunology (IRIC) and Cancer, Université de Montréal, 2950 Chemin de Polytechnique Pavillon, Marcelle-Coutu, Montréal, QC H3T 1J4, Canada; Department of Chemistry, Université de Montréal Pavillon Roger-Gaudry, 2900 Boulevard Édouard-Montpetit, Montr
  • Spinella JF; The Leucegene Project at Institute for Research in Immunology (IRIC) and Cancer, Université de Montréal, 2950 Chemin de Polytechnique Pavillon, Marcelle-Coutu, Montréal, QC H3T 1J4, Canada.
  • Corneau S; The Leucegene Project at Institute for Research in Immunology (IRIC) and Cancer, Université de Montréal, 2950 Chemin de Polytechnique Pavillon, Marcelle-Coutu, Montréal, QC H3T 1J4, Canada.
  • Mayotte N; The Leucegene Project at Institute for Research in Immunology (IRIC) and Cancer, Université de Montréal, 2950 Chemin de Polytechnique Pavillon, Marcelle-Coutu, Montréal, QC H3T 1J4, Canada.
  • Girard S; The Leucegene Project at Institute for Research in Immunology (IRIC) and Cancer, Université de Montréal, 2950 Chemin de Polytechnique Pavillon, Marcelle-Coutu, Montréal, QC H3T 1J4, Canada.
  • Frechette M; The Leucegene Project at Institute for Research in Immunology (IRIC) and Cancer, Université de Montréal, 2950 Chemin de Polytechnique Pavillon, Marcelle-Coutu, Montréal, QC H3T 1J4, Canada.
  • Blouin-Chagnon V; The Leucegene Project at Institute for Research in Immunology (IRIC) and Cancer, Université de Montréal, 2950 Chemin de Polytechnique Pavillon, Marcelle-Coutu, Montréal, QC H3T 1J4, Canada.
  • Leveillé K; The Leucegene Project at Institute for Research in Immunology (IRIC) and Cancer, Université de Montréal, 2950 Chemin de Polytechnique Pavillon, Marcelle-Coutu, Montréal, QC H3T 1J4, Canada.
  • Boivin I; The Leucegene Project at Institute for Research in Immunology (IRIC) and Cancer, Université de Montréal, 2950 Chemin de Polytechnique Pavillon, Marcelle-Coutu, Montréal, QC H3T 1J4, Canada.
  • MacRae T; The Leucegene Project at Institute for Research in Immunology (IRIC) and Cancer, Université de Montréal, 2950 Chemin de Polytechnique Pavillon, Marcelle-Coutu, Montréal, QC H3T 1J4, Canada.
  • Krosl J; The Leucegene Project at Institute for Research in Immunology (IRIC) and Cancer, Université de Montréal, 2950 Chemin de Polytechnique Pavillon, Marcelle-Coutu, Montréal, QC H3T 1J4, Canada.
  • Thiollier C; The Leucegene Project at Institute for Research in Immunology (IRIC) and Cancer, Université de Montréal, 2950 Chemin de Polytechnique Pavillon, Marcelle-Coutu, Montréal, QC H3T 1J4, Canada.
  • Lavallée VP; The Leucegene Project at Institute for Research in Immunology (IRIC) and Cancer, Université de Montréal, 2950 Chemin de Polytechnique Pavillon, Marcelle-Coutu, Montréal, QC H3T 1J4, Canada.
  • Kanshin E; The Leucegene Project at Institute for Research in Immunology (IRIC) and Cancer, Université de Montréal, 2950 Chemin de Polytechnique Pavillon, Marcelle-Coutu, Montréal, QC H3T 1J4, Canada.
  • Bertomeu T; The Leucegene Project at Institute for Research in Immunology (IRIC) and Cancer, Université de Montréal, 2950 Chemin de Polytechnique Pavillon, Marcelle-Coutu, Montréal, QC H3T 1J4, Canada.
  • Coulombe-Huntington J; The Leucegene Project at Institute for Research in Immunology (IRIC) and Cancer, Université de Montréal, 2950 Chemin de Polytechnique Pavillon, Marcelle-Coutu, Montréal, QC H3T 1J4, Canada.
  • St-Denis C; The Leucegene Project at Institute for Research in Immunology (IRIC) and Cancer, Université de Montréal, 2950 Chemin de Polytechnique Pavillon, Marcelle-Coutu, Montréal, QC H3T 1J4, Canada.
  • Bordeleau ME; The Leucegene Project at Institute for Research in Immunology (IRIC) and Cancer, Université de Montréal, 2950 Chemin de Polytechnique Pavillon, Marcelle-Coutu, Montréal, QC H3T 1J4, Canada.
  • Boucher G; The Leucegene Project at Institute for Research in Immunology (IRIC) and Cancer, Université de Montréal, 2950 Chemin de Polytechnique Pavillon, Marcelle-Coutu, Montréal, QC H3T 1J4, Canada.
  • Roux PP; The Leucegene Project at Institute for Research in Immunology (IRIC) and Cancer, Université de Montréal, 2950 Chemin de Polytechnique Pavillon, Marcelle-Coutu, Montréal, QC H3T 1J4, Canada; Department of Pathology & Cell Biology, Université de Montréal, 2900 Boulevard Édouard-Montpetit, Montréal
  • Lemieux S; The Leucegene Project at Institute for Research in Immunology (IRIC) and Cancer, Université de Montréal, 2950 Chemin de Polytechnique Pavillon, Marcelle-Coutu, Montréal, QC H3T 1J4, Canada; Department of Computer Science & Operations Research, Université de Montréal, 2950 Chemin de Polytechnique
  • Tyers M; The Leucegene Project at Institute for Research in Immunology (IRIC) and Cancer, Université de Montréal, 2950 Chemin de Polytechnique Pavillon, Marcelle-Coutu, Montréal, QC H3T 1J4, Canada.
  • Thibault P; The Leucegene Project at Institute for Research in Immunology (IRIC) and Cancer, Université de Montréal, 2950 Chemin de Polytechnique Pavillon, Marcelle-Coutu, Montréal, QC H3T 1J4, Canada.
  • Hébert J; The Leucegene Project at Institute for Research in Immunology (IRIC) and Cancer, Université de Montréal, 2950 Chemin de Polytechnique Pavillon, Marcelle-Coutu, Montréal, QC H3T 1J4, Canada; Leukemia Cell Bank of Quebec, 5415 Assumption Boulevard, Montréal, QC H1T 2M4, Canada; Division of Hematology,
  • Marinier A; The Leucegene Project at Institute for Research in Immunology (IRIC) and Cancer, Université de Montréal, 2950 Chemin de Polytechnique Pavillon, Marcelle-Coutu, Montréal, QC H3T 1J4, Canada; Department of Chemistry, Université de Montréal Pavillon Roger-Gaudry, 2900 Boulevard Édouard-Montpetit, Montr
  • Sauvageau G; The Leucegene Project at Institute for Research in Immunology (IRIC) and Cancer, Université de Montréal, 2950 Chemin de Polytechnique Pavillon, Marcelle-Coutu, Montréal, QC H3T 1J4, Canada; Leukemia Cell Bank of Quebec, 5415 Assumption Boulevard, Montréal, QC H1T 2M4, Canada; Division of Hematology,
Cancer Cell ; 36(1): 84-99.e8, 2019 07 08.
Article en En | MEDLINE | ID: mdl-31287994
ABSTRACT
To identify therapeutic targets in acute myeloid leukemia (AML), we chemically interrogated 200 sequenced primary specimens. Mubritinib, a known ERBB2 inhibitor, elicited strong anti-leukemic effects in vitro and in vivo. 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 an ETC complex I inhibitor and reveals the genetic landscape of OXPHOS dependency in AML.
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Texto completo: 1 Base de datos: MEDLINE Asunto principal: Oxazoles / Fosforilación Oxidativa / Triazoles / Leucemia Mieloide Aguda / Complejo I de Transporte de Electrón / Inhibidores de Proteínas Quinasas / Antineoplásicos Idioma: En Revista: Cancer Cell Asunto de la revista: NEOPLASIAS Año: 2019 Tipo del documento: Article
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Texto completo: 1 Base de datos: MEDLINE Asunto principal: Oxazoles / Fosforilación Oxidativa / Triazoles / Leucemia Mieloide Aguda / Complejo I de Transporte de Electrón / Inhibidores de Proteínas Quinasas / Antineoplásicos Idioma: En Revista: Cancer Cell Asunto de la revista: NEOPLASIAS Año: 2019 Tipo del documento: Article