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Identification of an Epi-metabolic dependency on EHMT2/G9a in T-cell acute lymphoblastic leukemia
Anna Montanaro1, Samuel Kitara2, Elisa Cerretani3
1Department of Medicine and Surgery, University of Parma, Parma, 43126, Italy.
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.
Insights
Targeting G9a, a key epigenetic regulator, offers a novel therapeutic strategy for T-cell acute lymphoblastic leukemia (T-ALL). Inhibiting G9a depletes T-ALL cells by disrupting their metabolic pathways, presenting a promising new avenue for treatment.
Area of Science:
- Epigenetics
- Molecular Biology
- Cancer Biology
Background:
- Genomic alterations in DNA methylation and histone modification genes are implicated in acute lymphoblastic leukemia (ALL).
- These epigenetic changes present potential therapeutic targets for ALL treatment.
Purpose of the Study:
- To identify and validate novel therapeutic targets in T-cell acute lymphoblastic leukemia (T-ALL).
- To investigate the role of G9a/EHMT2 in T-ALL pathogenesis and explore its potential as a drug target.
Main Methods:
- Utilized epigenome-centered shRNA and chemical screens to identify G9a/EHMT2 as a target.
- Validated G9a using CRISPR-Cas9 gene editing and tested G9a chemical inhibitors in vitro, 3D, and in vivo T-ALL models.
Main Results:
- G9a/EHMT2 was identified as a crucial target in T-ALL.
- G9a inhibition led to lysosomal biogenesis and autophagic degradation by suppressing sestrin2 (SESN2) and inhibiting glycogen synthase kinase-3 (GSK-3).
- Epigenetic regulation by G9a impacts glycolytic pathways in T-ALL.
Conclusions:
- Targeting G9a represents a viable strategy to suppress metabolic requirements in T-ALL cells.
- Inhibiting G9a can lead to metabolic exhaustion and cell death in T-ALL, offering a new therapeutic approach.
