Details

Autor(en) / Beteiligte

• Sykes, David B.
• Kfoury, Youmna S.
• Mercier, François E.
• Wawer, Mathias J.
• Law, Jason M.
• Haynes, Mark K.
• Lewis, Timothy A.
• Schajnovitz, Amir
• Jain, Esha
• Lee, Dongjun
• Meyer, Hanna
• Pierce, Kerry A.
• Tolliday, Nicola J.
• Waller, Anna
• Ferrara, Steven J.
• Eheim, Ashley L.
• Stoeckigt, Detlef
• Maxcy, Katrina L.
• Cobert, Julien M.
• Bachand, Jacqueline
• Szekely, Brian A.
• Mukherjee, Siddhartha
• Sklar, Larry A.
• Kotz, Joanne D.
• Clish, Clary B.
• Sadreyev, Ruslan I.
• Clemons, Paul A.
• Janzer, Andreas
• Schreiber, Stuart L.
• Scadden, David T.

Titel

Inhibition of Dihydroorotate Dehydrogenase Overcomes Differentiation Blockade in Acute Myeloid Leukemia

Ist Teil von

• Cell, 2016-09, Vol.167 (1), p.171-186.e15

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2016

Link zum Volltext

Quelle

EZB-FREE-00999 freely available EZB journals

Beschreibungen/Notizen

• 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. [Display omitted] •A phenotypic differentiation screen identifies DHODH as a target in AML•DHODH is a key link between pyrimidine synthesis and myeloid differentiation•DHODH represents a metabolic vulnerability across a range of AML subtypes•DHODH inhibitors show therapeutic potential in preclinical AML models. Inhibition of a metabolic enzyme involved in pyrimidine biosynthesis induces differentiation of leukemic cells, identifying a potential therapeutic approach for treating a range of acute myeloid leukemias, independent of their oncogenic driver.