UTX inhibition as selective epigenetic therapy against TAL1-driven T-cell acute lymphoblastic leukemia
- Aissa Benyoucef1,2,3,
- Carmen G. Palii1,3,
- Chaochen Wang4,
- Christopher J. Porter5,
- Alphonse Chu1,
- Fengtao Dai1,
- Véronique Tremblay3,6,
- Patricia Rakopoulos1,
- Kulwant Singh1,3,
- Suming Huang7,
- Francoise Pflumio8,9,10,
- Josée Hébert11,12,
- Jean-Francois Couture3,6,
- Theodore J. Perkins1,5,6,
- Kai Ge4,
- F. Jeffrey Dilworth1,2,3 and
- Marjorie Brand1,2,3
- 1The Sprott Center for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario K1H 8L6, Canada;
- 2Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario K1H 8L6, Canada;
- 3Ottawa Institute for Systems Biology, Ottawa, Ontario K1H 8L6, Canada;
- 4National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA;
- 5Ottawa Bioinformatics Core Facility, The Sprott Center for Stem Cell Research, Ottawa Hospital Research Institute, Ottawa, Ontario K1H 8L6, Canada;
- 6Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada;
- 7Department of Biochemistry and Molecular Biology, University of Florida College of Medicine, Gainesville, Florida 32610, USA;
- 8Commissariat 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;
- 9Institut National de la Santé et de la Recherche Médicale, U967, Fontenay-aux-Roses 92265, Paris, France;
- 10Université Paris Diderot, Sorbonne Paris Cité, Université Paris-Sud, UMR 967, Fontenay-aux-Roses 92265, Paris, France;
- 11Institute of Research in Immunology and Cancer, University of Montreal, Montreal, Quebec H3C 3J7, Canada;
- 12Maisonneuve-Rosemont Hospital, Montreal, Quebec H1T 2M4, Canada
- Corresponding author: mbrand{at}ohri.ca
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.
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Footnotes
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Supplemental material is available for this article.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.276790.115.
- Received December 21, 2015.
- Accepted January 29, 2016.
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