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 use...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Springer Nature
2022-05-01
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| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.202115203 |
| _version_ | 1827045174418604032 |
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| author | Joan So Alexander C Lewis Lorey K Smith Kym Stanley Rheana Franich David Yoannidis Lizzy Pijpers Pilar Dominguez Simon J Hogg Stephin J Vervoort Fiona C Brown Ricky W Johnstone Gabrielle McDonald Danielle B Ulanet Josh Murtie Emily Gruber Lev M Kats |
| author_facet | Joan So Alexander C Lewis Lorey K Smith Kym Stanley Rheana Franich David Yoannidis Lizzy Pijpers Pilar Dominguez Simon J Hogg Stephin J Vervoort Fiona C Brown Ricky W Johnstone Gabrielle McDonald Danielle B Ulanet Josh Murtie Emily Gruber Lev M Kats |
| author_sort | Joan So |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-07T18:23:23Z |
| format | Article |
| id | doaj.art-f74c466a9dec40289e640ece4bb498ee |
| institution | Directory Open Access Journal |
| issn | 1757-4676 1757-4684 |
| language | English |
| last_indexed | 2025-02-18T14:20:15Z |
| publishDate | 2022-05-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-f74c466a9dec40289e640ece4bb498ee2024-10-28T08:51:13ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842022-05-0114712010.15252/emmm.202115203Inhibition of pyrimidine biosynthesis targets protein translation in acute myeloid leukemiaJoan So0Alexander C Lewis1Lorey K Smith2Kym Stanley3Rheana Franich4David Yoannidis5Lizzy Pijpers6Pilar Dominguez7Simon J Hogg8Stephin J Vervoort9Fiona C Brown10Ricky W Johnstone11Gabrielle McDonald12Danielle B Ulanet13Josh Murtie14Emily Gruber15Lev M Kats16The Peter MacCallum Cancer CentreThe Peter MacCallum Cancer CentreThe Peter MacCallum Cancer CentreThe Peter MacCallum Cancer CentreThe Peter MacCallum Cancer CentreThe Peter MacCallum Cancer CentreThe Peter MacCallum Cancer CentreThe Peter MacCallum Cancer CentreHuman Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer CenterThe Peter MacCallum Cancer CentreAustralian Centre for Blood Diseases, Monash UniversityThe Peter MacCallum Cancer CentreServier PharmaceuticalsServier PharmaceuticalsServier PharmaceuticalsThe Peter MacCallum Cancer CentreThe Peter MacCallum Cancer CentreAbstract 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.https://doi.org/10.15252/emmm.202115203acute myeloid leukemiaDHODHleukemic stem cellsprotein translation |
| spellingShingle | Joan So Alexander C Lewis Lorey K Smith Kym Stanley Rheana Franich David Yoannidis Lizzy Pijpers Pilar Dominguez Simon J Hogg Stephin J Vervoort Fiona C Brown Ricky W Johnstone Gabrielle McDonald Danielle B Ulanet Josh Murtie Emily Gruber Lev M Kats Inhibition of pyrimidine biosynthesis targets protein translation in acute myeloid leukemia EMBO Molecular Medicine acute myeloid leukemia DHODH leukemic stem cells protein translation |
| title | Inhibition of pyrimidine biosynthesis targets protein translation in acute myeloid leukemia |
| title_full | Inhibition of pyrimidine biosynthesis targets protein translation in acute myeloid leukemia |
| title_fullStr | Inhibition of pyrimidine biosynthesis targets protein translation in acute myeloid leukemia |
| title_full_unstemmed | Inhibition of pyrimidine biosynthesis targets protein translation in acute myeloid leukemia |
| title_short | Inhibition of pyrimidine biosynthesis targets protein translation in acute myeloid leukemia |
| title_sort | inhibition of pyrimidine biosynthesis targets protein translation in acute myeloid leukemia |
| topic | acute myeloid leukemia DHODH leukemic stem cells protein translation |
| url | https://doi.org/10.15252/emmm.202115203 |
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