Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 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

Affiliations
Free article

Inhibition of Dihydroorotate Dehydrogenase Overcomes Differentiation Blockade in Acute Myeloid Leukemia

David B Sykes et al. Cell. .
Free article

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.

Comment in

Similar articles

See all similar articles

Cited by 69 articles

See all "Cited by" articles

Publication types

MeSH terms

LinkOut - more resources

Feedback