title: UTX inhibition as selective epigenetic therapy against TAL1-driven T-cell acute lymphoblastic leukemia.
abstract: T-cell acute lymphoblastic leukemia (T-ALL) is a heterogeneous group of hematological tumors composed of distinct subtypes that vary in their genetic abnormalities, gene expression signatures, and prognoses. However, it remains unclear whether T-ALL subtypes differ at the functional level, and, as such, T-ALL treatments are uniformly applied across subtypes, leading to variable responses between patients. Here we reveal the existence of a subtype-specific epigenetic vulnerability in T-ALL by which a particular subgroup of T-ALL characterized by expression of the oncogenic transcription factor TAL1 is uniquely sensitive to variations in the dosage and activity of the histone 3 Lys27 (H3K27) demethylase UTX/KDM6A. Specifically, we identify UTX as a coactivator of TAL1 and show that it acts as a major regulator of the TAL1 leukemic gene expression program. Furthermore, we demonstrate that UTX, previously described as a tumor suppressor in T-ALL, is in fact a pro-oncogenic cofactor essential for leukemia maintenance in TAL1-positive (but not TAL1-negative) T-ALL. Exploiting this subtype-specific epigenetic vulnerability, we propose a novel therapeutic approach based on UTX inhibition through in vivo administration of an H3K27 demethylase inhibitor that efficiently kills TAL1-positive primary human leukemia. These findings provide the first opportunity to develop personalized epigenetic therapy for T-ALL patients.
authors.affiliation: The Sprott Center for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario K1H 8L6, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario K1H 8L6, Canada; Ottawa Institute for Systems Biology, Ottawa, Ontario K1H 8L6, Canada;
authors.forename: Aissa
authors.initials: A
authors.lastname: Benyoucef
authors.affiliation: The Sprott Center for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario K1H 8L6, Canada; Ottawa Institute for Systems Biology, Ottawa, Ontario K1H 8L6, Canada;
authors.forename: Carmen G
authors.initials: CG
authors.lastname: Palii
authors.affiliation: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA;
authors.forename: Chaochen
authors.initials: C
authors.lastname: Wang
authors.affiliation: Ottawa Bioinformatics Core Facility, The Sprott Center for Stem Cell Research, Ottawa Hospital Research Institute, Ottawa, Ontario K1H 8L6, Canada;
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Porter
authors.affiliation: The Sprott Center for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario K1H 8L6, Canada;
authors.forename: Alphonse
authors.initials: A
authors.lastname: Chu
authors.affiliation: The Sprott Center for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario K1H 8L6, Canada;
authors.forename: Fengtao
authors.initials: F
authors.lastname: Dai
authors.affiliation: Ottawa Institute for Systems Biology, Ottawa, Ontario K1H 8L6, Canada; Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada;
authors.forename: Véronique
authors.initials: V
authors.lastname: Tremblay
authors.affiliation: The Sprott Center for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario K1H 8L6, Canada;
authors.forename: Patricia
authors.initials: P
authors.lastname: Rakopoulos
authors.affiliation: The Sprott Center for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario K1H 8L6, Canada; Ottawa Institute for Systems Biology, Ottawa, Ontario K1H 8L6, Canada;
authors.forename: Kulwant
authors.initials: K
authors.lastname: Singh
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Florida College of Medicine, Gainesville, Florida 32610, USA;
authors.forename: Suming
authors.initials: S
authors.lastname: Huang
authors.affiliation: Commissariat á l'Energie Atomique et aux Energies Alternatives, Direction des Sciences du Vivant (DSV)-Institut de Recherche en Radiobiologie Cellulaire et Moléculaire (IRCM)-Stem Cells and Radiation Department (SCSR)-Laboratory of Hematopoietic Stem Cells and Leukemia (LSHL), U967, Fontenay-aux-Roses 92265, Paris, France; Institut National de la Santé et de la Recherche Médicale, U967, Fontenay-aux-Roses 92265, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Université Paris-Sud, UMR 967, Fontenay-aux-Roses 92265, Paris, France;
authors.forename: Francoise
authors.initials: F
authors.lastname: Pflumio
authors.affiliation: Institute of Research in Immunology and Cancer, University of Montreal, Montreal, Quebec H3C 3J7, Canada; Maisonneuve-Rosemont Hospital, Montreal, Quebec H1T 2M4, Canada.
authors.forename: Josée
authors.initials: J
authors.lastname: Hébert
authors.affiliation: Ottawa Institute for Systems Biology, Ottawa, Ontario K1H 8L6, Canada; Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada;
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Couture
authors.affiliation: The Sprott Center for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario K1H 8L6, Canada; Ottawa Bioinformatics Core Facility, The Sprott Center for Stem Cell Research, Ottawa Hospital Research Institute, Ottawa, Ontario K1H 8L6, Canada; Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada;
authors.forename: Theodore J
authors.initials: TJ
authors.lastname: Perkins
authors.affiliation: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA;
authors.forename: Kai
authors.initials: K
authors.lastname: Ge
authors.affiliation: The Sprott Center for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario K1H 8L6, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario K1H 8L6, Canada; Ottawa Institute for Systems Biology, Ottawa, Ontario K1H 8L6, Canada;
authors.forename: F Jeffrey
authors.initials: FJ
authors.lastname: Dilworth
authors.affiliation: The Sprott Center for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario K1H 8L6, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario K1H 8L6, Canada; Ottawa Institute for Systems Biology, Ottawa, Ontario K1H 8L6, Canada;
authors.forename: Marjorie
authors.initials: M
authors.lastname: Brand
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D055785:Gene Knockdown Techniques; D015316:Genetic Therapy; D056466:Histone Demethylases / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000503:physiopathology / Q000628:therapy*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D056466:Histone Demethylases; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; C067143:TAL1 protein, human; C523998:KDM6A protein, human
keywords: TAL1; UTX; epigenetics; histone demethylase inhibitor; histone demethylation; leukemia