ATF3 coordinates serine and nucleotide metabolism to drive cell cycle progression in acute myeloid leukemia.
Mol Cell
; 81(13): 2752-2764.e6, 2021 07 01.
Article
em En
| MEDLINE
| ID: mdl-34081901
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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Serina
/
Leucemia Mieloide Aguda
/
Ciclo Celular
/
Fator 3 Ativador da Transcrição
/
Proteínas de Neoplasias
/
Nucleotídeos
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Mol Cell
Assunto da revista:
BIOLOGIA MOLECULAR
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
Estados Unidos