Inhibition of pyrimidine biosynthesis targets protein translation in acute myeloid leukemia Journal Article
| Authors: | So, J.; Lewis, A. C.; Smith, L. K.; Stanley, K.; Franich, R.; Yoannidis, D.; Pijpers, L.; Dominguez, P.; Hogg, S. J.; Vervoort, S. J.; Brown, F. C.; Johnstone, R. W.; McDonald, G.; Ulanet, D. B.; Murtie, J.; Gruber, E.; Kats, L. M. |
| Article Title: | Inhibition of pyrimidine biosynthesis targets protein translation in acute myeloid leukemia |
| 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. © 2022 The Authors. Published under the terms of the CC BY 4.0 license. |
| Keywords: | leukemia, myeloid, acute; metabolism; enzyme inhibitor; pyrimidines; protein synthesis; enzyme inhibitors; protein biosynthesis; pyrimidine derivative; oxidoreductase; leukemic stem cells; acute myeloid leukemia; oxidoreductases acting on ch-ch group donors; protein translation; humans; human; dihydroorotate dehydrogenase; dhodh |
| Journal Title: | EMBO Molecular Medicine |
| Volume: | 14 |
| Issue: | 7 |
| ISSN: | 1757-4676 |
| Publisher: | Wiley Blackwell |
| Date Published: | 2022-07-07 |
| Start Page: | e15203 |
| Language: | English |
| DOI: | 10.15252/emmm.202115203 |
| PUBMED: | 35514210 |
| PROVIDER: | scopus |
| PMCID: | PMC9260210 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 August 2022 -- Source: Scopus |
