Inhibition of Dihydroorotate Dehydrogenase Overcomes Differentiation Blockade in Acute Myeloid Leukemia

• Published in: Cell Vol. 167; no. 1; pp. 171 - 186.e15
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 22.09.2016
• Subjects: acute myeloid leukemia; Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - isolation & purification; Antineoplastic Agents - therapeutic use; brequinar; Cell Differentiation; developmental stages; differentiation; dihydroorotate dehydrogenase; enzyme inhibition; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - isolation & purification; Enzyme Inhibitors - therapeutic use; gene expression regulation; genes; high-throughput screen; High-Throughput Screening Assays; Homeodomain Proteins - genetics; HoxA9; Humans; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - pathology; leukemia-initiating cell; metabolic inhibitor; Mice; Molecular Targeted Therapy; Myeloid Cells - pathology; myeloid leukemia; Oxidoreductases Acting on CH-CH Group Donors - antagonists & inhibitors; Oxidoreductases Acting on CH-CH Group Donors - metabolism; phenotype; phenotypic screen; Pyrimidines - metabolism; Small Molecule Libraries - chemistry; Small Molecule Libraries - isolation & purification; Small Molecule Libraries - therapeutic use; Xenograft Model Antitumor Assays; high-throughput screen; dihydroorotate dehydrogenase; differentiation; HoxA9; acute myeloid leukemia; leukemia-initiating cell; phenotypic screen; brequinar; metabolic inhibitor
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2016.08.057

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.