Format

Send to

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

Inhibition of Dihydroorotate Dehydrogenase Overcomes Differentiation Blockade in Acute Myeloid Leukemia.

Author information

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

PMID:
27641501
DOI:
10.1016/j.cell.2016.08.057
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center