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Di Marcantonio D , Martinez E , Kanefsky JS , Huhn JM , Gabbasov R , Gupta A , Krais JJ , Peri S , Tan Y , Skorski T , Dorrance A , Garzon R , Goldman AR , Tang HY , Johnson N , Sykes SM
ATF3 coordinates serine and nucleotide metabolism to drive cell cycle progression in acute myeloid leukemia
Mol Cell. 2021 May 25;81(13) :2752-2764 e6
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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.
Notes
1097-4164 Di Marcantonio, Daniela Martinez, Esteban Kanefsky, Joice S Huhn, Jacklyn M Gabbasov, Rashid Gupta, Anushk Krais, John J Peri, Suraj Tan, YinFei Skorski, Tomasz Dorrance, Adrienne Garzon, Ramiro Goldman, Aaron R Tang, Hsin-Yao Johnson, Neil Sykes, Stephen M Journal Article United States Mol Cell. 2021 May 25:S1097-2765(21)00365-8. doi: 10.1016/j.molcel.2021.05.008.