[HTML][HTML] Inhibition of dihydroorotate dehydrogenase overcomes differentiation blockade in acute myeloid leukemia

DB Sykes, YS Kfoury, FE Mercier, MJ Wawer, JM Law… - Cell, 2016 - cell.com
DB Sykes, YS Kfoury, FE Mercier, MJ Wawer, JM Law, MK Haynes, TA Lewis, A Schajnovitz
Cell, 2016cell.com
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 …
Summary
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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