title: Contrasting roles of histone 3 lysine 27 demethylases in acute lymphoblastic leukaemia.
abstract: T-cell acute lymphoblastic leukaemia (T-ALL) is a haematological malignancy with a dismal overall prognosis, including a relapse rate of up to 25%, mainly because of the lack of non-cytotoxic targeted therapy options. Drugs that target the function of key epigenetic factors have been approved in the context of haematopoietic disorders, and mutations that affect chromatin modulators in a variety of leukaemias have recently been identified; however, 'epigenetic' drugs are not currently used for T-ALL treatment. Recently, we described that the polycomb repressive complex 2 (PRC2) has a tumour-suppressor role in T-ALL. Here we delineated the role of the histone 3 lysine 27 (H3K27) demethylases JMJD3 and UTX in T-ALL. We show that JMJD3 is essential for the initiation and maintenance of T-ALL, as it controls important oncogenic gene targets by modulating H3K27 methylation. By contrast, we found that UTX functions as a tumour suppressor and is frequently genetically inactivated in T-ALL. Moreover, we demonstrated that the small molecule inhibitor GSKJ4 (ref. 5) affects T-ALL growth, by targeting JMJD3 activity. These findings show that two proteins with a similar enzymatic function can have opposing roles in the context of the same disease, paving the way for treating haematopoietic malignancies with a new category of epigenetic inhibitors.
authors.affiliation: 1] Howard Hughes Medical Institute and Department of Pathology, NYU School of Medicine, New York, New York 10016, USA [2] NYU Cancer Institute and Helen L. and Martin S. Kimmel Center for Stem Cell Biology, NYU School of Medicine, New York, New York 10016, USA [3].
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Ntziachristos
authors.affiliation: 1] Howard Hughes Medical Institute and Department of Pathology, NYU School of Medicine, New York, New York 10016, USA [2] Center for Health Informatics and Bioinformatics, NYU School of Medicine, New York, New York 10016, USA [3].
authors.forename: Aristotelis
authors.initials: A
authors.lastname: Tsirigos
authors.affiliation: 1] Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA [2] Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [3].
authors.forename: G Grant
authors.initials: GG
authors.lastname: Welstead
authors.affiliation: 1] Howard Hughes Medical Institute and Department of Pathology, NYU School of Medicine, New York, New York 10016, USA [2] NYU Cancer Institute and Helen L. and Martin S. Kimmel Center for Stem Cell Biology, NYU School of Medicine, New York, New York 10016, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Trimarchi
authors.affiliation: 1] Howard Hughes Medical Institute and Department of Pathology, NYU School of Medicine, New York, New York 10016, USA [2] NYU Cancer Institute and Helen L. and Martin S. Kimmel Center for Stem Cell Biology, NYU School of Medicine, New York, New York 10016, USA.
authors.forename: Sofia
authors.initials: S
authors.lastname: Bakogianni
authors.affiliation: Institute for Cancer Genetics, Columbia University Medical Center, New York, New York 10032, USA.
authors.forename: Luyao
authors.initials: L
authors.lastname: Xu
authors.affiliation: 1] Howard Hughes Medical Institute and Department of Pathology, NYU School of Medicine, New York, New York 10016, USA [2] NYU Cancer Institute and Helen L. and Martin S. Kimmel Center for Stem Cell Biology, NYU School of Medicine, New York, New York 10016, USA.
authors.forename: Evangelia
authors.initials: E
authors.lastname: Loizou
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Linda
authors.initials: L
authors.lastname: Holmfeldt
authors.affiliation: 1] Howard Hughes Medical Institute and Department of Pathology, NYU School of Medicine, New York, New York 10016, USA [2] NYU Cancer Institute and Helen L. and Martin S. Kimmel Center for Stem Cell Biology, NYU School of Medicine, New York, New York 10016, USA.
authors.forename: Alexandros
authors.initials: A
authors.lastname: Strikoudis
authors.affiliation: 1] Howard Hughes Medical Institute and Department of Pathology, NYU School of Medicine, New York, New York 10016, USA [2] NYU Cancer Institute and Helen L. and Martin S. Kimmel Center for Stem Cell Biology, NYU School of Medicine, New York, New York 10016, USA.
authors.forename: Bryan
authors.initials: B
authors.lastname: King
authors.affiliation: 1] Howard Hughes Medical Institute and Department of Pathology, NYU School of Medicine, New York, New York 10016, USA [2] NYU Cancer Institute and Helen L. and Martin S. Kimmel Center for Stem Cell Biology, NYU School of Medicine, New York, New York 10016, USA.
authors.forename: Jasper
authors.initials: J
authors.lastname: Mullenders
authors.affiliation: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Jared
authors.initials: J
authors.lastname: Becksfort
authors.affiliation: 1] Howard Hughes Medical Institute and Department of Pathology, NYU School of Medicine, New York, New York 10016, USA [2] NYU Cancer Institute and Helen L. and Martin S. Kimmel Center for Stem Cell Biology, NYU School of Medicine, New York, New York 10016, USA.
authors.forename: Jelena
authors.initials: J
authors.lastname: Nedjic
authors.affiliation: Montefiore Medical Center North, Bronx, New York, New York 10467, USA.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Paietta
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Martin S
authors.initials: MS
authors.lastname: Tallman
authors.affiliation: 1] Technion, Israel Institute of Technology, Haifa 31096, Israel [2] Shaare Zedek Medical Center, Jerusalem 9103102, Israel.
authors.forename: Jacob M
authors.initials: JM
authors.lastname: Rowe
authors.affiliation: Functional Genomics of Cancer Unit, Division of Molecular Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, 20132 Milan, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Tonon
authors.affiliation: 1] Laboratory of Host Defense, WPI Immunology Frontier Research Center (WPI IFReC), Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan [2] Department of Host Defense, Research Institute for Microbial Diseases (RIMD), Osaka University, 3-1Yamada-oka, Suita, Osaka 565-0871, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Satoh
authors.affiliation: Epinova DPU, Immuno-Inflammation Therapy Area, GlaxoSmithKline R&D, Medicines Research Centre, GunnelsWood Road, Stevenage SG1 2NY, UK.
authors.forename: Laurens
authors.initials: L
authors.lastname: Kruidenier
authors.affiliation: Epinova DPU, Immuno-Inflammation Therapy Area, GlaxoSmithKline R&D, Medicines Research Centre, GunnelsWood Road, Stevenage SG1 2NY, UK.
authors.forename: Rab
authors.initials: R
authors.lastname: Prinjha
authors.affiliation: 1] Laboratory of Host Defense, WPI Immunology Frontier Research Center (WPI IFReC), Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan [2] Department of Host Defense, Research Institute for Microbial Diseases (RIMD), Osaka University, 3-1Yamada-oka, Suita, Osaka 565-0871, Japan.
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.affiliation: 1] Institute for Cancer Genetics, Columbia University Medical Center, New York, New York 10032, USA [2] Center for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium.
authors.forename: Pieter
authors.initials: P
authors.lastname: Van Vlierberghe
authors.affiliation: 1] Institute for Cancer Genetics, Columbia University Medical Center, New York, New York 10032, USA [2] Department of Pathology, Columbia University Medical Center, New York, New York 10032, USA [3] Department of Pediatrics, Columbia University Medical Center, New York, New York 10032, USA.
authors.forename: Adolfo A
authors.initials: AA
authors.lastname: Ferrando
authors.affiliation: 1] Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA [2] Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Jaenisch
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Charles G
authors.initials: CG
authors.lastname: Mullighan
authors.affiliation: 1] Howard Hughes Medical Institute and Department of Pathology, NYU School of Medicine, New York, New York 10016, USA [2] NYU Cancer Institute and Helen L. and Martin S. Kimmel Center for Stem Cell Biology, NYU School of Medicine, New York, New York 10016, USA.
authors.forename: Iannis
authors.initials: I
authors.lastname: Aifantis
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D044127:Epigenesis, Genetic / Q000187:drug effects; D056466:Histone Demethylases / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000737:chemistry / Q000378:metabolism; D056484:Jumonji Domain-Containing Histone Demethylases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism; D008745:Methylation / Q000187:drug effects; D051379:Mice; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D011743:Pyrimidines / Q000494:pharmacology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D001552:Benzazepines; C000593030:GSK-J4; D006657:Histones; D011743:Pyrimidines; D025521:Tumor Suppressor Proteins; D056466:Histone Demethylases; D056484:Jumonji Domain-Containing Histone Demethylases; C111778:Utx protein, mouse; C523761:Kdm6b protein, mouse; D008239:Lysine