Identification of an Epi-metabolic dependency on EHMT2/G9a in T-cell acute lymphoblastic leukemia.
Cell Death Dis
; 13(6): 551, 2022 06 17.
Article
em En
| MEDLINE
| ID: mdl-35710782
ABSTRACT
Genomic studies have identified recurrent somatic alterations in genes involved in DNA methylation and post-translational histone modifications in acute lymphoblastic leukemia (ALL), suggesting new opportunities for therapeutic interventions. In this study, we identified G9a/EHMT2 as a potential target in T-ALL through the intersection of epigenome-centered shRNA and chemical screens. We subsequently validated G9a with low-throughput CRISPR-Cas9-based studies targeting the catalytic G9a SET-domain and the testing of G9a chemical inhibitors in vitro, 3D, and in vivo T-ALL models. Mechanistically we determined that G9a repression promotes lysosomal biogenesis and autophagic degradation associated with the suppression of sestrin2 (SESN2) and inhibition of glycogen synthase kinase-3 (GSK-3), suggesting that in T-ALL glycolytic dependent pathways are at least in part under epigenetic control. Thus, targeting G9a represents a strategy to exhaust the metabolic requirement of T-ALL cells.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Histona-Lisina N-Metiltransferase
/
Leucemia-Linfoma Linfoblástico de Células T Precursoras
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article