Inhibition of dihydroorotate dehydrogenase overcomes differentiation blockade in acute myeloid leukemia
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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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Inhibition of DHODH can induce differentiation in a myeloid cell screen involving HoxA9-enforced differentiation arrest.
“Recently, a myeloid cell screen involving HoxA9-enforced differentiation arrest found that inhibition of dihydroorotate dehydrogenase (DHODH), an enzyme in the pyrimidine biosynthesis pathway (Figure 1b), can induce differentiation (Sykes et al., 2016).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Sykes et al., 2016
Brequinar sodium, a DHODH inhibitor approved for autoimmune disease, overcomes myeloid differentiation blockade and reduces leukemic cell burden in patient-derived xenografts and syngeneic mouse AML models of diverse genetic subtypes.
“Treatment with brequinar sodium (BRQ), an inhibitor of DHODH that is approved to treat autoimmune disease, is able to overcome myeloid differentiation blockade and reduces leukemic cell burden in patient-derived xenografts and syngeneic mouse AML models of diverse genetic subtypes.”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Sykes et al., 2016
Targeting DHODH depletes uridine and downstream metabolites, and providing uridine is sufficient to maintain myeloid arrest even in the presence of DHODH-targeting compounds.
“Targeting DHODH depletes uridine and downstream metabolites, and providing uridine is sufficient to maintain myeloid arrest, even in the presence of compounds targeting DHODH.”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Sykes et al., 2016
DHODH is targeted in autoimmune disorders and inhibition suppresses myeloid differentiation of AML cells.
“DHODH is targeted in autoimmune disorders and inhibition suppresses myeloid differentiation of AML cells.75”
From The multifaceted contributions of mitochondria to cellular metabolism (2018) · cites this paper as [75]
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- Authors
- Sykes, D. B., Kfoury, Y. S., Mercier, F. E., Wawer, M. J., Law, J. M., Haynes, M. K., Lewis, T. A., Schajnovitz, A., Jain, E., Lee, D., Meyer, H., Pierce, K. A., Tolliday, N. J., Waller, A., Ferrara, S. J., Eheim, A. L., Stoeckigt, D., Maxcy, K. L., Cobert, J. M., Bachand, J., Szekely, B. A., Mukherjee, S., Sklar, L. A., Kotz, J. D., Clish, C. B., Sadreyev, R. I., Clemons, P. A., Janzer, A., Schreiber, S. L., & Scadden, D. T.
- Affiliations
- Harvard University (US)
- Broad Institute (US)
- University of New Mexico (US)
- Massachusetts General Hospital (US)
- Bayer (Germany) (DE)
- Columbia University Irving Medical Center (US)
- Corresponding author
- Sykes, David B.
- Scadden, David T.
- ORCID
- Sykes, David B.
- Kfoury, Youmna S.
- Mercier, François E.
- Wawer, Mathias J.
- Lewis, Timothy A.
- Jain, Esha
- Lee, Dongjun
- Pierce, Kerry A.
- Waller, Anna
- Ferrara, Steven J.
- Cobert, Julien M.
- Bachand, Jacqueline
- Mukherjee, Siddhartha
- Sklar, Larry A.
- Kotz, Joanne D.
- Clish, Clary B.
- Sadreyev, Ruslan I.
- Clemons, Paul A.
- Schreiber, Stuart L.
- Scadden, David T.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2016-09
- Volume
- 167
- Issue
- 1
- Pages
- 171-186.e15
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC7360335
- OpenAlex
- W2520159331
- Cited by
- 500
- References
- 55
- Citations by year
- 2026: 45 · 2025: 44 · 2024: 48 · 2023: 46 · 2022: 79 · 2021: 58 · 2020: 62 · 2019: 41 · 2018: 34 · 2017: 27 · 2016: 4 · 2012: 1
- FWCI
- 33.94
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- European Hematology Association (TRTH86)
- National Institutes of Health (1s10od012027-01a1)
- National Institute of Mental Health (U54MH084690)
- National Institute on Drug Abuse (R03DA032471)
- National Human Genome Research Institute (U54HG005032)
- National Cancer Institute (K08CA201640)
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
- Keywords
- acute myeloid leukemia, dihydroorotate dehydrogenase, DHODH inhibitors, HOXA9, leukemia-initiating cells, phenotypic screening, drug target identification
- MeSH terms
- Dihydroorotate Dehydrogenase, Animals, Antineoplastic Agents, Cell Differentiation, Enzyme Inhibitors, Humans, Pyrimidines, Leukemia, Myeloid, Acute, Homeodomain Proteins, Myeloid Cells, Xenograft Model Antitumor Assays, Oxidoreductases Acting on CH-CH Group Donors, Mice, Small Molecule Libraries, High-Throughput Screening Assays, Molecular Targeted Therapy
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