title: Isocitrate dehydrogenase 1 mutations prime the all-trans retinoic acid myeloid differentiation pathway in acute myeloid leukemia.
abstract: Acute myeloid leukemia (AML) is characterized by the accumulation of malignant blasts with impaired differentiation programs caused by recurrent mutations, such as the isocitrate dehydrogenase (IDH) mutations found in 15% of AML patients. These mutations result in the production of the oncometabolite (R)-2-hydroxyglutarate (2-HG), leading to a hypermethylation phenotype that dysregulates hematopoietic differentiation. In this study, we identified mutant R132H IDH1-specific gene signatures regulated by key transcription factors, particularly CEBPα, involved in myeloid differentiation and retinoid responsiveness. We show that treatment with all-trans retinoic acid (ATRA) at clinically achievable doses markedly enhanced terminal granulocytic differentiation in AML cell lines, primary patient samples, and a xenograft mouse model carrying mutant IDH1. Moreover, treatment with a cell-permeable form of 2-HG sensitized wild-type IDH1 AML cells to ATRA-induced myeloid differentiation, whereas inhibition of 2-HG production significantly reduced ATRA effects in mutant IDH1 cells. ATRA treatment specifically decreased cell viability and induced apoptosis of mutant IDH1 blasts in vitro. ATRA also reduced tumor burden of mutant IDH1 AML cells xenografted in NOD-Scid-IL2rγ(null)mice and markedly increased overall survival, revealing a potent antileukemic effect of ATRA in the presence of IDH1 mutation. This therapeutic strategy holds promise for this AML patient subgroup in future clinical studies.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), Cancer Research Center of Toulouse, U1037, F-31024 Toulouse, France Université de Toulouse, F-31300 Toulouse, France Service d'Hématologie, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer Toulouse Oncopole, F-31059 Toulouse, France.
authors.forename: Héléna
authors.initials: H
authors.lastname: Boutzen
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), Cancer Research Center of Toulouse, U1037, F-31024 Toulouse, France Université de Toulouse, F-31300 Toulouse, France.
authors.forename: Estelle
authors.initials: E
authors.lastname: Saland
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), Cancer Research Center of Toulouse, U1037, F-31024 Toulouse, France Université de Toulouse, F-31300 Toulouse, France.
authors.forename: Clément
authors.initials: C
authors.lastname: Larrue
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), Cancer Research Center of Toulouse, U1037, F-31024 Toulouse, France Université de Toulouse, F-31300 Toulouse, France.
authors.forename: Fabienne
authors.initials: F
authors.lastname: de Toni
authors.affiliation: Université de Toulouse III Paul Sabatier, Institut National des Sciences Appliquées, UPS, Institut National Polytechnique, L'Ingénierie des Systèmes Biologiques et des Procédés, F-31077 Toulouse, France Institut National de la Recherche Agronomique (INRA), UMR792, Ingénierie des Systèmes Biologiques et des Procédés, F-31400 Toulouse, France Centre National de la Recherche Scientifique, UMR5504, F-31400 Toulouse, France.
authors.forename: Lara
authors.initials: L
authors.lastname: Gales
authors.affiliation: CEA/DSV/iBiTec-S/SPI, Laboratoire d'Etude du Métabolisme des Médicaments, MetaboHUB-Paris, F-91191 Gif-sur-Yvette, France.
authors.forename: Florence A
authors.initials: FA
authors.lastname: Castelli
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), Cancer Research Center of Toulouse, U1037, F-31024 Toulouse, France Université de Toulouse, F-31300 Toulouse, France.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Cathebas
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), Cancer Research Center of Toulouse, U1037, F-31024 Toulouse, France Université de Toulouse, F-31300 Toulouse, France.
authors.forename: Sonia
authors.initials: S
authors.lastname: Zaghdoudi
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), Cancer Research Center of Toulouse, U1037, F-31024 Toulouse, France Université de Toulouse, F-31300 Toulouse, France.
authors.forename: Lucille
authors.initials: L
authors.lastname: Stuani
authors.affiliation: Genomics Research Unit, Centre de Recherche Public de la Santé, 1526 Luxembourg City, Luxembourg.
authors.forename: Tony
authors.initials: T
authors.lastname: Kaoma
authors.affiliation: INSERM, U1194, Institut de Recherche en Cancérologie de Montpellier, F-34298 Montpellier, France Université de Montpellier, F-34298 Montpellier, France Institut régional du Cancer Montpellier, F-34298 Montpellier, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Riscal
authors.affiliation: Organic Synthesis Core Facility, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
authors.forename: Guangli
authors.initials: G
authors.lastname: Yang
authors.affiliation: Sorbonne Universités, Université Pierre-et-Marie-Curie (UPMC) Paris VI​, UMR-S 938, CDR Saint-Antoine, F-75012 Paris, France INSERM, UMR-S938, CDR Saint-Antoine, F-75012 Paris, France Sorbonne Universités, UPMC Paris VI, GRC n°07, Groupe de Recherche Clinique sur les Myéloproliférations Aiguës et Chroniques MyPAC, F-75012 Paris, France AP-HP, Hôpital Saint-Antoine, F-75012 Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Hirsch
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), Cancer Research Center of Toulouse, U1037, F-31024 Toulouse, France Université de Toulouse, F-31300 Toulouse, France.
authors.forename: Marion
authors.initials: M
authors.lastname: David
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), Cancer Research Center of Toulouse, U1037, F-31024 Toulouse, France Université de Toulouse, F-31300 Toulouse, France Service d'Hématologie, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer Toulouse Oncopole, F-31059 Toulouse, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: De Mas-Mansat
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), Cancer Research Center of Toulouse, U1037, F-31024 Toulouse, France Université de Toulouse, F-31300 Toulouse, France Service d'Hématologie, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer Toulouse Oncopole, F-31059 Toulouse, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Delabesse
authors.affiliation: Genomics Research Unit, Centre de Recherche Public de la Santé, 1526 Luxembourg City, Luxembourg.
authors.forename: Laurent
authors.initials: L
authors.lastname: Vallar
authors.affiliation: Sorbonne Universités, Université Pierre-et-Marie-Curie (UPMC) Paris VI​, UMR-S 938, CDR Saint-Antoine, F-75012 Paris, France INSERM, UMR-S938, CDR Saint-Antoine, F-75012 Paris, France Sorbonne Universités, UPMC Paris VI, GRC n°07, Groupe de Recherche Clinique sur les Myéloproliférations Aiguës et Chroniques MyPAC, F-75012 Paris, France AP-HP, Hôpital Saint-Antoine, F-75012 Paris, France.
authors.forename: François
authors.initials: F
authors.lastname: Delhommeau
authors.affiliation: INRA, UMR1331, Toxalim, Research Centre in Food Toxicology, F-31027 Toulouse, France Université de Toulouse, INP, Toxalim, UMR1331, F-31027 Toulouse, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Jouanin
authors.affiliation: Organic Synthesis Core Facility, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
authors.forename: Ouathek
authors.initials: O
authors.lastname: Ouerfelli
authors.affiliation: INSERM, U1194, Institut de Recherche en Cancérologie de Montpellier, F-34298 Montpellier, France Université de Montpellier, F-34298 Montpellier, France Institut régional du Cancer Montpellier, F-34298 Montpellier, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Le Cam
authors.affiliation: INSERM, U1194, Institut de Recherche en Cancérologie de Montpellier, F-34298 Montpellier, France Université de Montpellier, F-34298 Montpellier, France Institut régional du Cancer Montpellier, F-34298 Montpellier, France.
authors.forename: Laetitia K
authors.initials: LK
authors.lastname: Linares
authors.affiliation: CEA/DSV/iBiTec-S/SPI, Laboratoire d'Etude du Métabolisme des Médicaments, MetaboHUB-Paris, F-91191 Gif-sur-Yvette, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Junot
authors.affiliation: Université de Toulouse III Paul Sabatier, Institut National des Sciences Appliquées, UPS, Institut National Polytechnique, L'Ingénierie des Systèmes Biologiques et des Procédés, F-31077 Toulouse, France Institut National de la Recherche Agronomique (INRA), UMR792, Ingénierie des Systèmes Biologiques et des Procédés, F-31400 Toulouse, France Centre National de la Recherche Scientifique, UMR5504, F-31400 Toulouse, France.
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Portais
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), Cancer Research Center of Toulouse, U1037, F-31024 Toulouse, France Université de Toulouse, F-31300 Toulouse, France Service d'Hématologie, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer Toulouse Oncopole, F-31059 Toulouse, France.
authors.forename: François
authors.initials: F
authors.lastname: Vergez
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), Cancer Research Center of Toulouse, U1037, F-31024 Toulouse, France Université de Toulouse, F-31300 Toulouse, France Service d'Hématologie, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer Toulouse Oncopole, F-31059 Toulouse, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Récher
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), Cancer Research Center of Toulouse, U1037, F-31024 Toulouse, France Université de Toulouse, F-31300 Toulouse, France jean-emmanuel.sarry@inserm.fr.
authors.forename: Jean-Emmanuel
authors.initials: JE
authors.lastname: Sarry
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001752:Blast Crisis / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects* / Q000235:genetics; D002470:Cell Survival; D005260:Female; D006098:Granulocytes / Q000378:metabolism / Q000473:pathology; D018922:HL-60 Cells; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D020125:Mutation, Missense; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D014212:Tretinoin / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; C515848:CEBPA protein, human; D009363:Neoplasm Proteins; D014212:Tretinoin; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human