See all articles by Lucille StuaniUniversity of Toulouse 3, Paul Sabatier University - Toulouse Cancer Research Center
University of Toulouse 3, Paul Sabatier University - Toulouse Cancer Research Center
University of Toulouse 1 - Laboratory of Engineering of Biological Systems and Processes (LISBP)
University of Toulouse 1 - Laboratory of Engineering of Biological Systems and Processes (LISBP)
National Infrastructure of Metabolomics and Fluxomics - MetaToul-MetaboHUB
University of Toulouse 3, Paul Sabatier University - Toulouse Cancer Research Center
University of Toulouse 3, Paul Sabatier University - Toulouse Cancer Research Center
University of Toulouse 3, Paul Sabatier University - Toulouse Cancer Research Center
University of Toulouse 1 - Laboratory of Engineering of Biological Systems and Processes (LISBP)
Aix-Marseille University - Institut Paoli-Calmettes
MetaboHUB-Paris - Laboratoire d’Etude du Métabolisme des Médicaments
Proteome and Genome Reserch Unit
University of Toulouse 3, Paul Sabatier University - Toulouse Cancer Research Center
University of Toulouse 3, Paul Sabatier University - Toulouse Cancer Research Center
University of Montpellier - Institute for Cancer Research in Montpellier
University of Toulouse 3, Paul Sabatier University - Toulouse Cancer Research Center
University of Toulouse 3, Paul Sabatier University - Toulouse Cancer Research Center
University of Texas at Houston - Department of Genomic Medicine
University of Texas at Houston - Department of Genomic Medicine
University of Toulouse 3, Paul Sabatier University - Toulouse Cancer Research Center
University of Toulouse 3, Paul Sabatier University - Toulouse Cancer Research Center
University of Toulouse 3, Paul Sabatier University - Toulouse Cancer Research Center
University of Toulouse 3, Paul Sabatier University - Toulouse Cancer Research Center
University of Toulouse 3, Paul Sabatier University - Toulouse Cancer Research Center
University of Toulouse 3, Paul Sabatier University - Toulouse Cancer Research Center
University of Bordeaux - Fruit Biology and Pathology
University of Toulouse 1 - Toxalim INRA laboratory
University of Montpellier - Institute for Cancer Research in Montpellier
University of Toulouse 3, Paul Sabatier University - Toulouse Cancer Research Center
University of Montpellier - Institute for Cancer Research in Montpellier
University of Texas at Houston - Department of Genomic Medicine
Louisiana State University, Baton Rouge - School of Medicine; University of Texas at Houston - Department of Genomic Medicine
University of Toulouse 1 - Laboratory of Engineering of Biological Systems and Processes (LISBP)
University of Toulouse 1 - Laboratory of Engineering of Biological Systems and Processes (LISBP)
MetaboHUB-Paris - Laboratoire d’Etude du Métabolisme des Médicaments
University of Montpellier - Institute for Cancer Research in Montpellier
University of Pennsylvania - Division of Hematology/Oncology
University of Pennsylvania - Division of Hematology/Oncology
Aix-Marseille University
Centre Hospitalier Universitaire (CHU) de Bordeaux - Clinical Hematology Service
Centre Hospitalier Universitaire (CHU) de Bordeaux - Clinical Hematology Service
Centre Hospitalier Universitaire (CHU) de Bordeaux - Biological Hematology Service
Aix-Marseille University - Institut Paoli-Calmettes
MetaboHUB-Paris - Laboratoire d’Etude du Métabolisme des Médicaments
University of Montpellier - Institute for Cancer Research in Montpellier
University of Montpellier - Laboratory of Physical Measurements
National Infrastructure of Metabolomics and Fluxomics - MetaToul-MetaboHUB
Onco-Occitanie Regional Oncology Network
University of Texas at Houston - Department of Genomic Medicine
University of Texas at Houston - Department of Leukemia
University of Texas at Houston - Department of Leukemia
University of Texas at Houston - MD Anderson Cancer Center
University of Montpellier - Institute for Cancer Research in Montpellier
University of Bordeaux - Fruit Biology and Pathology
Aix-Marseille University - Institut Paoli-Calmettes
University of Toulouse 3, Paul Sabatier University - Toulouse Cancer Research Center
University of Toulouse 1 - Laboratory of Engineering of Biological Systems and Processes (LISBP)
National Infrastructure of Metabolomics and Fluxomics - MetaToul-MetaboHUB
University of Toulouse 3, Paul Sabatier University - Toulouse Cancer Research Center
University of Toulouse 1 - Laboratory of Engineering of Biological Systems and Processes (LISBP)
University of Toulouse 3, Paul Sabatier University - Toulouse Cancer Research Center
Abstract
Isocitrate dehydrogenases (IDH) are involved in redox control and central metabolism. We hypothesized that key metabolic fluxes are selectively reprogrammed to maintain biosynthetic homeostasis and lower drug responses in IDH mutant acute myeloid leukemia cells. Here we show that metabolic reprogramming initiated by IDH1 mutation leads to marked increases in glucose, glutamine and fatty acid catabolism that along with enhancement of wild-type IDH enzyme activity contribute to provision of α-KG required for 2-HG synthesis and to replenish Krebs cycle intermediates for biosynthetic reactions, oxygen consumption and ATP production. Mechanistically, this occurs through both methylation-driven CEBPα activation of FAO and reprogramming of systemic metabolic fluxes through other pathways that augment catabolic flexibility. Consequently, this catabolic flexibility enhances Krebs cycle and OxPHOS activities that are not necessarily rescued by IDH mutant inhibitors or 2-HG reduction. This renders IDH1 mutant cells more resistant to chemotherapeutics but more susceptible to mitochondrial inhibition. Our findings provide a scientific rationale for innovative combinatory targeted therapies to treat this subgroup of patients, especially those unresponsive to or relapsing from IDH mutant-specific inhibitors.
Stuani, Lucille and Sabatier, Marie and Millard, Pierre and Palama, Tony and Poupin, Nathalie and Saland, Estelle and Bosc, Claudie and Tonini, Laure and Gales, Lara and Montersino, Camille and Castelli, Florence and Kaoma, Tony and Farge, Thomas and Broin, Nicolas and Cissé, Madi and Hosseini, Mohsen and Larrue, Clément and Wang, Feng and Baran, Natalia and Saint-Laurent, Nathalie and Mouchel, Pierre-Luc and Fraisse, Marine and Gotanègre, Mathilde and Gadaud, Noémie and Aroua, Nesrine and Cassan, Cédric and Fernando, Laurent and Turtoi, Evgenia and Boutzen, Héléna and Gayte, Laurie and Morita, Kiyomi and Futreal, Andrew M. and Heuillet, Maud and Peyriga, Lindsay and Chu-Van, Emeline and Le Cam, Laurent and Carroll, Martin and Selak, Mary A. and Vey, Norbert and Calmettes, Claire and Pigneux, Arnaud and Bidet, Audrey and Castellano, Rémy and Junot, Christophe and Turtoi, Andrei and Cazals, Guillaume and Bertrand-Michel, Justine and Bories, Pierre and Marszalek, Joe and Dinardo, Courtney and Takahashi, Koichi and Konopleva, Marina and Linares, Laetitia K. and Gibon, Yves and Collette, Yves and Lopez, Frédéric and Bellvert, Floriant and Jourdan, Fabien and Récher, Christian and Portais, Jean-Charles and Sarry, Jean-Emmanuel, IDH1 Mutation Enhances Catabolic Flexibility and Mitochondrial Dependencies to Favor Drug Resistance in Acute Myeloid Leukemia (September 26, 2018). Available at SSRN:
https://ssrn.com/abstract=3255557 or
http://dx.doi.org/10.2139/ssrn.3255557