| Literature DB >> 27641501 |
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.
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.Entities:
Keywords: HoxA9; acute myeloid leukemia; brequinar; differentiation; dihydroorotate dehydrogenase; high-throughput screen; leukemia-initiating cell; metabolic inhibitor; phenotypic screen
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Year: 2016 PMID： 27641501 PMCID： PMC7360335 DOI： 10.1016/j.cell.2016.08.057
Source DB: PubMed Journal: Cell ISSN： 0092-8674 Impact factor: 41.582