Inhibition of Dihydroorotate Dehydrogenase Overcomes Differentiation Blockade in Acute Myeloid Leukemia

David B Sykes; Youmna S Kfoury; François E Mercier; Mathias J Wawer; Jason M Law; Mark K Haynes; Timothy A Lewis; Amir Schajnovitz; Esha Jain; Dongjun Lee; Hanna Meyer; Kerry A Pierce; Nicola J Tolliday; Anna Waller; Steven J Ferrara; Ashley L Eheim; Detlef Stoeckigt; Katrina L Maxcy; Julien M Cobert; Jacqueline Bachand; Brian A Szekely; Siddhartha Mukherjee; Larry A Sklar; Joanne D Kotz; Clary B Clish; Ruslan I Sadreyev; Paul A Clemons; Andreas Janzer; Stuart L Schreiber; David T Scadden

doi:10.1016/j.cell.2016.08.057

Inhibition of Dihydroorotate Dehydrogenase Overcomes Differentiation Blockade in Acute Myeloid Leukemia

Cell. 2016 Sep 22;167(1):171-186.e15. doi: 10.1016/j.cell.2016.08.057. Epub 2016 Sep 15.

Authors

David B Sykes¹, Youmna S Kfoury², François E Mercier², Mathias J Wawer³, Jason M Law⁴, Mark K Haynes⁵, Timothy A Lewis⁶, Amir Schajnovitz², Esha Jain⁷, Dongjun Lee², Hanna Meyer⁸, Kerry A Pierce⁹, Nicola J Tolliday³, Anna Waller⁵, Steven J Ferrara³, Ashley L Eheim⁸, Detlef Stoeckigt⁸, Katrina L Maxcy⁷, Julien M Cobert⁷, Jacqueline Bachand⁷, Brian A Szekely⁷, Siddhartha Mukherjee¹⁰, Larry A Sklar⁵, Joanne D Kotz⁶, Clary B Clish⁹, Ruslan I Sadreyev¹¹, Paul A Clemons⁶, Andreas Janzer⁸, Stuart L Schreiber¹², David T Scadden¹³

Affiliations

¹ 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.
² 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.
³ Center for the Development of Therapeutics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁴ Center for the Science of Therapeutics, Broad Institute, Cambridge, MA 02142, USA; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
⁵ Center for Molecular Discovery, University of New Mexico, Albuquerque, NM 87131, USA.
⁶ Center for the Science of Therapeutics, Broad Institute, Cambridge, MA 02142, USA.
⁷ Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
⁸ Bayer Pharma AG, Berlin 13353, Germany.
⁹ Metabolite Profiling Platform, Broad Institute, Cambridge, MA 02142, USA.
¹⁰ Irving Cancer Research Center, Columbia University School of Medicine, New York, NY 10032, USA.
¹¹ 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.
¹² 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.
¹³ 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.

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.

Keywords: HoxA9; acute myeloid leukemia; brequinar; differentiation; dihydroorotate dehydrogenase; high-throughput screen; leukemia-initiating cell; metabolic inhibitor; phenotypic screen.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / chemistry
Antineoplastic Agents / isolation & purification
Antineoplastic Agents / therapeutic use*
Cell Differentiation
Dihydroorotate Dehydrogenase
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / isolation & purification
Enzyme Inhibitors / therapeutic use*
High-Throughput Screening Assays
Homeodomain Proteins / genetics
Humans
Leukemia, Myeloid, Acute / drug therapy*
Leukemia, Myeloid, Acute / genetics
Leukemia, Myeloid, Acute / pathology*
Mice
Molecular Targeted Therapy*
Myeloid Cells / pathology
Oxidoreductases Acting on CH-CH Group Donors / antagonists & inhibitors*
Oxidoreductases Acting on CH-CH Group Donors / metabolism
Pyrimidines / metabolism
Small Molecule Libraries / chemistry
Small Molecule Libraries / isolation & purification
Small Molecule Libraries / therapeutic use
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents
Dihydroorotate Dehydrogenase
Enzyme Inhibitors
Homeodomain Proteins
Pyrimidines
Small Molecule Libraries
homeobox protein HOXA9
Oxidoreductases Acting on CH-CH Group Donors
pyrimidine

Abstract

Publication types

MeSH terms

Substances

Grants and funding