Identification of an Epi-metabolic dependency on EHMT2/G9a in T-cell acute lymphoblastic leukemia.
Anna MontanaroSamuel KitaraElisa CerretaniMatteo MarchesiniChiara RompiettiLuca PagliaroAndrea GherliAngela SuMaria Laura MinchilloMariafrancesca CaputiRodanthi FioretzakiBruno LorussoLinda RossGabriela AlexeElena MasselliMarina MarozziFederica Maria Angela RizziRoberta La StarzaCristina MecucciYan XiongJian JinAngela FalcoBirgit KnoechelFranco AversaOlivia CandiniFederico QuainiPaolo SportolettiKimberly StegmaierGiovanni RotiPublished in: Cell death & disease (2022)
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.
Keyphrases
- dna methylation
- acute lymphoblastic leukemia
- genome wide
- copy number
- crispr cas
- gene expression
- allogeneic hematopoietic stem cell transplantation
- induced apoptosis
- genome editing
- cancer therapy
- case control
- cell death
- signaling pathway
- pi k akt
- high throughput
- risk assessment
- cell proliferation
- drug delivery
- human health
- acute myeloid leukemia
- endoplasmic reticulum stress