ATF3 coordinates serine and nucleotide metabolism to drive cell cycle progression in acute myeloid leukemia
Open accessAbstract
Metabolic reprogramming is a common feature of many human cancers, including acute myeloid leukemia (AML). However, the upstream regulators that promote AML metabolic reprogramming and the benefits conferred to leukemia cells by these metabolic changes remain largely unknown. We report that the transcription factor ATF3 coordinates serine and nucleotide metabolism to maintain cell cycling, survival, and the differentiation blockade in AML. Analysis of mouse and human AML models demonstrate that ATF3 directly activates the transcription of genes encoding key enzymatic regulators of serine synthesis, one-carbon metabolism, and de novo purine and pyrimidine synthesis. Total steady-state polar metabolite and heavy isotope tracing analyses show that ATF3 inhibition reduces de novo serine synthesis, impedes the incorporation of serine-derived carbons into newly synthesized purines, and disrupts pyrimidine metabolism. Importantly, exogenous nucleotide supplementation mitigates the anti-leukemia effects of ATF3 inhibition. Together, these findings reveal the dependence of AML on ATF3-regulated serine and nucleotide metabolism.
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ATF3 coordinates serine and nucleotide metabolism.
“and also coordinates serine and nucleotide metabolism [40]”
From 20-Hydroxyecdysone Boosts Energy Production and Biosynthetic Processes in Non-Transformed Mouse Cells (2024) · cites this paper as [40]
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- Authors
- Di Marcantonio, D., Martinez, E., Kanefsky, J. S., Huhn, J. M., Gabbasov, R., Gupta, A., Krais, J. J., Peri, S., Tan, Y., Skorski, T., Dorrance, A., Garzon, R., Goldman, A. R., Tang, H.-Y., Johnson, N., & Sykes, S. M.
- Affiliations
- Fox Chase Cancer Center (US)
- The Ohio State University Wexner Medical Center (US)
- The Wistar Institute (US)
- Corresponding author
- Sykes, Stephen M.
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2021-07
- Volume
- 81
- Issue
- 13
- Pages
- 2752-2764.e6
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC8452149
- OpenAlex
- W3165884354
- Cited by
- 67
- References
- 51
- Citations by year
- 2026: 9 · 2025: 18 · 2024: 12 · 2023: 17 · 2022: 9 · 2021: 2
- FWCI
- 3.97
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 365 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Molecular Cell (publishedVersion)
- SSRN Electronic Journal (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (S10 OD023586, RSG-18-195-01-DDC, HL150190, CA010815, K99 CA241370, R01CA214799, R01 CA227830, CA237286, R01 CA244179, R50 CA221838, TRP 6565-19)
- American Cancer Society (S10 OD023586, RSG-18-195-01-DDC, HL150190, CA010815, K99 CA241370, R01CA214799, R01 CA227830, CA237286, R01 CA244179, R50 CA221838, TRP 6565-19)
- NHLBI (S10 OD023586, RSG-18-195-01-DDC, HL150190, CA010815, K99 CA241370, R01CA214799, R01 CA227830, CA237286, R01 CA244179, R50 CA221838, TRP 6565-19)
- NCI (S10 OD023586, RSG-18-195-01-DDC, HL150190, CA010815, K99 CA241370, R01CA214799, R01 CA227830, CA237286, R01 CA244179, R50 CA221838, TRP 6565-19)
- Leukemia and Lymphoma Society (S10 OD023586, RSG-18-195-01-DDC, HL150190, CA010815, K99 CA241370, R01CA214799, R01 CA227830, CA237286, R01 CA244179, R50 CA221838, TRP 6565-19)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Keywords
- ATF3, acute myeloid leukemia, metabolic reprogramming, serine metabolism, nucleotide metabolism, one-carbon metabolism, purine biosynthesis, pyrimidine synthesis, cell cycle progression, transcriptional regulation, nucleotide supplementation, isotope tracing
- MeSH terms
- Cell Cycle, Humans, Neoplasm Proteins, Nucleotides, Serine, Leukemia, Myeloid, Acute, Cell Line, Tumor, Activating Transcription Factor 3
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