title: Inhibition of Dihydroorotate Dehydrogenase Overcomes Differentiation Blockade in Acute Myeloid Leukemia.
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.
authors.affiliation: 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 02138, USA. Electronic address: dbsykes@mgh.harvard.edu.
authors.forename: David B
authors.initials: DB
authors.lastname: Sykes
authors.affiliation: 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.
authors.forename: Youmna S
authors.initials: YS
authors.lastname: Kfoury
authors.affiliation: 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.
authors.forename: François E
authors.initials: FE
authors.lastname: Mercier
authors.affiliation: Center for the Development of Therapeutics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Mathias J
authors.initials: MJ
authors.lastname: Wawer
authors.affiliation: Center for the Science of Therapeutics, Broad Institute, Cambridge, MA 02142, USA; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Law
authors.affiliation: Center for Molecular Discovery, University of New Mexico, Albuquerque, NM 87131, USA.
authors.forename: Mark K
authors.initials: MK
authors.lastname: Haynes
authors.affiliation: Center for the Science of Therapeutics, Broad Institute, Cambridge, MA 02142, USA.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Lewis
authors.affiliation: 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.
authors.forename: Amir
authors.initials: A
authors.lastname: Schajnovitz
authors.affiliation: Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Esha
authors.initials: E
authors.lastname: Jain
authors.affiliation: 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.
authors.forename: Dongjun
authors.initials: D
authors.lastname: Lee
authors.affiliation: Bayer Pharma AG, Berlin 13353, Germany.
authors.forename: Hanna
authors.initials: H
authors.lastname: Meyer
authors.affiliation: Metabolite Profiling Platform, Broad Institute, Cambridge, MA 02142, USA.
authors.forename: Kerry A
authors.initials: KA
authors.lastname: Pierce
authors.affiliation: Center for the Development of Therapeutics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Tolliday
authors.affiliation: Center for Molecular Discovery, University of New Mexico, Albuquerque, NM 87131, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Waller
authors.affiliation: Center for the Development of Therapeutics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Ferrara
authors.affiliation: Bayer Pharma AG, Berlin 13353, Germany.
authors.forename: Ashley L
authors.initials: AL
authors.lastname: Eheim
authors.affiliation: Bayer Pharma AG, Berlin 13353, Germany.
authors.forename: Detlef
authors.initials: D
authors.lastname: Stoeckigt
authors.affiliation: Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Katrina L
authors.initials: KL
authors.lastname: Maxcy
authors.affiliation: Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Julien M
authors.initials: JM
authors.lastname: Cobert
authors.affiliation: Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Bachand
authors.affiliation: Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Brian A
authors.initials: BA
authors.lastname: Szekely
authors.affiliation: Irving Cancer Research Center, Columbia University School of Medicine, New York, NY 10032, USA.
authors.forename: Siddhartha
authors.initials: S
authors.lastname: Mukherjee
authors.affiliation: Center for Molecular Discovery, University of New Mexico, Albuquerque, NM 87131, USA.
authors.forename: Larry A
authors.initials: LA
authors.lastname: Sklar
authors.affiliation: Center for the Science of Therapeutics, Broad Institute, Cambridge, MA 02142, USA.
authors.forename: Joanne D
authors.initials: JD
authors.lastname: Kotz
authors.affiliation: Metabolite Profiling Platform, Broad Institute, Cambridge, MA 02142, USA.
authors.forename: Clary B
authors.initials: CB
authors.lastname: Clish
authors.affiliation: 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.
authors.forename: Ruslan I
authors.initials: RI
authors.lastname: Sadreyev
authors.affiliation: Center for the Science of Therapeutics, Broad Institute, Cambridge, MA 02142, USA.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Clemons
authors.affiliation: Bayer Pharma AG, Berlin 13353, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Janzer
authors.affiliation: 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.
authors.forename: Stuart L
authors.initials: SL
authors.lastname: Schreiber
authors.affiliation: 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 02138, USA. Electronic address: dscadden@mgh.harvard.edu.
authors.forename: David T
authors.initials: DT
authors.lastname: Scadden
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000302:isolation & purification / Q000627:therapeutic use*; D002454:Cell Differentiation; D000090722:Dihydroorotate Dehydrogenase; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000627:therapeutic use*; D057166:High-Throughput Screening Assays; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D051379:Mice; D058990:Molecular Targeted Therapy; D022423:Myeloid Cells / Q000473:pathology; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry / Q000302:isolation & purification / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D000090722:Dihydroorotate Dehydrogenase; D004791:Enzyme Inhibitors; D018398:Homeodomain Proteins; D011743:Pyrimidines; D054852:Small Molecule Libraries; C097899:homeobox protein HOXA9; D044925:Oxidoreductases Acting on CH-CH Group Donors; C030986:pyrimidine
keywords: HoxA9; acute myeloid leukemia; brequinar; differentiation; dihydroorotate dehydrogenase; high-throughput screen; leukemia-initiating cell; metabolic inhibitor; phenotypic screen