UTX inhibition as selective epigenetic therapy against TAL1-driven T-cell acute lymphoblastic leukemia. - Literature - Data resources

26944678

UTX inhibition as selective epigenetic therapy against TAL1-driven T-cell acute lymphoblastic leukemia.

Genes Dev, 2016/3/01;30(5):508-21.

Benyoucef A^[1], Palii CG^[2], Wang C^[3], Porter CJ^[4], Chu A^[5], Dai F^[5], Tremblay V^[6], Rakopoulos P^[5], Singh K^[2], Huang S^[7], Pflumio F^[8], Hébert J^[9], Couture JF^[6], Perkins TJ^[10], Ge K^[3], Dilworth FJ^[1], Brand M^[1]

Affiliations

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;
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;
National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA;
Ottawa Bioinformatics Core Facility, The Sprott Center for Stem Cell Research, Ottawa Hospital Research Institute, Ottawa, Ontario K1H 8L6, Canada;
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; Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada;
Department of Biochemistry and Molecular Biology, University of Florida College of Medicine, Gainesville, Florida 32610, USA;
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;
Institute of Research in Immunology and Cancer, University of Montreal, Montreal, Quebec H3C 3J7, Canada; Maisonneuve-Rosemont Hospital, Montreal, Quebec H1T 2M4, Canada.
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;

PMID: 26944678DOI: 10.1101/gad.276790.115

Impact factor: 12.89

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.

Keywords: TAL1; UTX; epigenetics; histone demethylase inhibitor; histone demethylation; leukemia

MeSH terms

Basic Helix-Loop-Helix Transcription Factors; Cell Line, Tumor; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Genetic Therapy; Histone Demethylases; Humans; Nuclear Proteins; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Proto-Oncogene Proteins; T-Cell Acute Lymphocytic Leukemia Protein 1

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