Inhibition of pyrimidine biosynthesis targets protein translation in acute myeloid leukemia

So, J; Lewis, AC; Smith, LK; Stanley, K; Franich, R; Yoannidis, D; Pijpers, L; Dominguez, P; Hogg, SJ; Vervoort, SJ; Brown, FC; Johnstone, RW; McDonald, G; Ulanet, DB; Murtie, J; Gruber, E; Kats, LM

Author(s): So, J; Lewis, AC; Smith, LK; Stanley, K; Franich, R; Yoannidis, D; Pijpers, L; Dominguez, P; Hogg, SJ; Vervoort, SJ; Brown, FC; Johnstone, RW; McDonald, G; Ulanet, DB; Murtie, J; Gruber, E; Kats, LM;
Details: Publication Year 2022-07-07,Volume 14,Issue #7,Page e15203
Journal Title: EMBO Molecular Medicine
Publication Type: Research article
Abstract: The mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) catalyzes one of the rate-limiting steps in de novo pyrimidine biosynthesis, a pathway that provides essential metabolic precursors for nucleic acids, glycoproteins, and phospholipids. DHODH inhibitors (DHODHi) are clinically used for autoimmune diseases and are emerging as a novel class of anticancer agents, especially in acute myeloid leukemia (AML) where pyrimidine starvation was recently shown to reverse the characteristic differentiation block in AML cells. Herein, we show that DHODH blockade rapidly shuts down protein translation in leukemic stem cells (LSCs) and has potent and selective activity against multiple AML subtypes. Moreover, we find that ablation of CDK5, a gene that is recurrently deleted in AML and related disorders, increases the sensitivity of AML cells to DHODHi. Our studies provide important molecular insights and identify a potential biomarker for an emerging strategy to target AML.
Keywords: Dihydroorotate Dehydrogenase; Enzyme Inhibitors/pharmacology; Humans; *Leukemia, Myeloid, Acute; *Oxidoreductases Acting on CH-CH Group Donors/metabolism; Protein Biosynthesis; Pyrimidines/pharmacology; Dhodh; acute myeloid leukemia; leukemic stem cells; protein translation
Department(s): Laboratory Research
PubMed ID: 35514210
Publisher's Version: https://doi.org/10.15252/emmm.202115203
Open Access at Publisher's Site: https://doi.org/10.15252/emmm.202115203
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2025-04-11 03:02:36

Last Modified: 2025-04-11 03:05:16