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Inhibition of Dihydroorotate Dehydrogenase Overcomes Differentiation Blockade in Acute Myeloid Leukemia

2016; Cell Press; Volume: 167; Issue: 1 Linguagem: Inglês

10.1016/j.cell.2016.08.057

1097-4172

David B. Sykes, Youmna Kfoury, François 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 Tolliday, Anna Waller, Steven Ferrara, Ashley Eheim, Detlef Stoeckigt, Katrina Maxcy, Julien Cobert, Jacqueline Bachand, Brian A. Szekely, Siddhartha Mukherjee, Larry A. Sklar, Joanne Kotz, Clary B. Clish, Ruslan I. Sadreyev, Paul A. Clemons, Andreas Janzer, Stuart L. Schreiber, David T. Scadden,

HIV/AIDS drug development and treatment

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.