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Inhibition of Dihydroorotate Dehydrogenase Overcomes Differentiation Blockade in Acute Myeloid Leukemia.
Sykes, David B; Kfoury, Youmna S; Mercier, François E; Wawer, Mathias J; Law, Jason M; Haynes, Mark K; Lewis, Timothy A; Schajnovitz, Amir; Jain, Esha; Lee, Dongjun; Meyer, Hanna; Pierce, Kerry A; Tolliday, Nicola J; Waller, Anna; Ferrara, Steven J; Eheim, Ashley L; Stoeckigt, Detlef; Maxcy, Katrina L; Cobert, Julien M; Bachand, Jacqueline; Szekely, Brian A; Mukherjee, Siddhartha; Sklar, Larry A; Kotz, Joanne D; Clish, Clary B; Sadreyev, Ruslan I; Clemons, Paul A; Janzer, Andreas; Schreiber, Stuart L; Scadden, David T.
Afiliação
  • Sykes DB; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Cambridge, MA 02
  • Kfoury YS; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
  • Mercier FE; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
  • Wawer MJ; Center for the Development of Therapeutics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Law JM; Center for the Science of Therapeutics, Broad Institute, Cambridge, MA 02142, USA; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
  • Haynes MK; Center for Molecular Discovery, University of New Mexico, Albuquerque, NM 87131, USA.
  • Lewis TA; Center for the Science of Therapeutics, Broad Institute, Cambridge, MA 02142, USA.
  • Schajnovitz A; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
  • Jain E; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
  • Lee D; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
  • Meyer H; Bayer Pharma AG, Berlin 13353, Germany.
  • Pierce KA; Metabolite Profiling Platform, Broad Institute, Cambridge, MA 02142, USA.
  • Tolliday NJ; Center for the Development of Therapeutics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Waller A; Center for Molecular Discovery, University of New Mexico, Albuquerque, NM 87131, USA.
  • Ferrara SJ; Center for the Development of Therapeutics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Eheim AL; Bayer Pharma AG, Berlin 13353, Germany.
  • Stoeckigt D; Bayer Pharma AG, Berlin 13353, Germany.
  • Maxcy KL; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
  • Cobert JM; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
  • Bachand J; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
  • Szekely BA; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
  • Mukherjee S; Irving Cancer Research Center, Columbia University School of Medicine, New York, NY 10032, USA.
  • Sklar LA; Center for Molecular Discovery, University of New Mexico, Albuquerque, NM 87131, USA.
  • Kotz JD; Center for the Science of Therapeutics, Broad Institute, Cambridge, MA 02142, USA.
  • Clish CB; Metabolite Profiling Platform, Broad Institute, Cambridge, MA 02142, USA.
  • Sadreyev RI; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
  • Clemons PA; Center for the Science of Therapeutics, Broad Institute, Cambridge, MA 02142, USA.
  • Janzer A; Bayer Pharma AG, Berlin 13353, Germany.
  • Schreiber SL; Center for the Science of Therapeutics, Broad Institute, Cambridge, MA 02142, USA; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA; Howard Hughes Medical Institute, Cambridge, MA 02138, USA.
  • Scadden DT; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Cambridge, MA 02
Cell ; 167(1): 171-186.e15, 2016 Sep 22.
Article em En | MEDLINE | ID: mdl-27641501
ABSTRACT
While acute myeloid leukemia (AML) comprises many disparate genetic subtypes, one shared hallmark is the arrest of leukemic myeloblasts at an immature and self-renewing stage of development. Therapies that overcome differentiation arrest represent a powerful treatment strategy. We leveraged the observation that the majority of AML, despite their genetically heterogeneity, share in the expression of HoxA9, a gene normally downregulated during myeloid differentiation. Using a conditional HoxA9 model system, we performed a high-throughput phenotypic screen and defined compounds that overcame differentiation blockade. Target identification led to the unanticipated discovery that inhibition of the enzyme dihydroorotate dehydrogenase (DHODH) enables myeloid differentiation in human and mouse AML models. In vivo, DHODH inhibitors reduced leukemic cell burden, decreased levels of leukemia-initiating cells, and improved survival. These data demonstrate the role of DHODH as a metabolic regulator of differentiation and point to its inhibition as a strategy for overcoming differentiation blockade in AML.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Leucemia Mieloide Aguda / Oxirredutases atuantes sobre Doadores de Grupo CH-CH / Inibidores Enzimáticos / Terapia de Alvo Molecular / Antineoplásicos Limite: Animals / Humans Idioma: En Revista: Cell Ano de publicação: 2016 Tipo de documento: Article
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Leucemia Mieloide Aguda / Oxirredutases atuantes sobre Doadores de Grupo CH-CH / Inibidores Enzimáticos / Terapia de Alvo Molecular / Antineoplásicos Limite: Animals / Humans Idioma: En Revista: Cell Ano de publicação: 2016 Tipo de documento: Article