@article{d4cce7a501a643468d92bcdce04ddf67,
title = "ATF3 coordinates serine and nucleotide metabolism to drive cell cycle progression in acute myeloid leukemia",
abstract = "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.",
keywords = "AML, ATF3, ATF4, cell cycle, differentiation, leukemia, metabolism, purines, pyrimidines, serine",
author = "{Di Marcantonio}, Daniela and Esteban Martinez and Kanefsky, {Joice S.} and Huhn, {Jacklyn M.} and Rashid Gabbasov and Anushk Gupta and Krais, {John J.} and Suraj Peri and Tan, {Yin Fei} and Tomasz Skorski and Adrienne Dorrance and Ramiro Garzon and Goldman, {Aaron R.} and Tang, {Hsin Yao} and Neil Johnson and Sykes, {Stephen M.}",
note = "Funding Information: We thank the Laboratory Animal, Cell Culture, and Flow Cytometry facilities at Fox Chase Cancer Center. The Wistar Proteomics and Metabolomics Core Facility was supported by Cancer Center Support Grants CA010815 and S10 OD023586. The following individuals are supported by NIH grants: D.D.M. (K99 CA241370), T.S. (R01 CA244179 and CA237286), N.J. (R01CA214799 and HL150190), H.-Y.T. (R50 CA221838), and S.M.S. (R01 CA227830). T.S. is also supported by the Leukemia and Lymphoma Society (TRP 6565-19), and S.M.S. is also supported by the American Cancer Society (RSG-18-195-01-DDC). Conceptualization, D.D.M. E.M. and S.M.S.; formal analysis, S.P. Y.F.T. A.R.G. and H.-Y.T.; investigation, D.D.M. E.M. J.S.K. J.M.H. R. Gabbasov, A.G. J.J.K. Y.F.T. and A.R.G.; resources, T.S. A.D. and R. Garzon; writing – original draft, D.D.M. E.M. and S.M.S.; supervision, N.J. H.-Y.T. and S.M.S. S.P. is currently an employee of Merck Research Laboratories and R. Gabbasov is currently an employee of Carisma Therapeutics. All other authors declare no competing interests. Funding Information: We thank the Laboratory Animal, Cell Culture, and Flow Cytometry facilities at Fox Chase Cancer Center. The Wistar Proteomics and Metabolomics Core Facility was supported by Cancer Center Support Grants CA010815 and S10 OD023586. The following individuals are supported by NIH grants: D.D.M. ( K99 CA241370 ), T.S. ( R01 CA244179 and CA237286 ), N.J. ( R01CA214799 and HL150190 ), H.-Y.T. ( R50 CA221838 ), and S.M.S. ( R01 CA227830 ). T.S. is also supported by the Leukemia and Lymphoma Society ( TRP 6565-19 ), and S.M.S. is also supported by the American Cancer Society ( RSG-18-195-01-DDC ). Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",
year = "2021",
month = jul,
day = "1",
doi = "10.1016/j.molcel.2021.05.008",
language = "English",
volume = "81",
pages = "2752--2764.e6",
journal = "Molecular cell",
issn = "1097-2765",
number = "13",
}