Cell Death and Disease (Jun 2022)
Identification of an Epi-metabolic dependency on EHMT2/G9a in T-cell acute lymphoblastic leukemia
- Anna Montanaro,
- Samuel Kitara,
- Elisa Cerretani,
- Matteo Marchesini,
- Chiara Rompietti,
- Luca Pagliaro,
- Andrea Gherli,
- Angela Su,
- Maria Laura Minchillo,
- Mariafrancesca Caputi,
- Rodanthi Fioretzaki,
- Bruno Lorusso,
- Linda Ross,
- Gabriela Alexe,
- Elena Masselli,
- Marina Marozzi,
- Federica Maria Angela Rizzi,
- Roberta La Starza,
- Cristina Mecucci,
- Yan Xiong,
- Jian Jin,
- Angela Falco,
- Birgit Knoechel,
- Franco Aversa,
- Olivia Candini,
- Federico Quaini,
- Paolo Sportoletti,
- Kimberly Stegmaier,
- Giovanni Roti
Affiliations
- Anna Montanaro
- Department of Medicine and Surgery, University of Parma
- Samuel Kitara
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School
- Elisa Cerretani
- Department of Medical Science, University of Ferrara
- Matteo Marchesini
- Department of Medicine and Surgery, University of Parma
- Chiara Rompietti
- Department of Medicine, Hematology and Clinical Immunology, University of Perugia
- Luca Pagliaro
- Department of Medicine and Surgery, University of Parma
- Andrea Gherli
- Department of Medicine and Surgery, University of Parma
- Angela Su
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School
- Maria Laura Minchillo
- Department of Medicine and Surgery, University of Parma
- Mariafrancesca Caputi
- Department of Medicine and Surgery, University of Parma
- Rodanthi Fioretzaki
- Department of Medicine and Surgery, University of Parma
- Bruno Lorusso
- Department of Medicine and Surgery, University of Parma
- Linda Ross
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School
- Gabriela Alexe
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School
- Elena Masselli
- Department of Medicine and Surgery, University of Parma
- Marina Marozzi
- Department of Medicine and Surgery, University of Parma
- Federica Maria Angela Rizzi
- Department of Medicine and Surgery, University of Parma
- Roberta La Starza
- Department of Medicine, Hematology and Clinical Immunology, University of Perugia
- Cristina Mecucci
- Department of Medicine, Hematology and Clinical Immunology, University of Perugia
- Yan Xiong
- Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai
- Jian Jin
- Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai
- Angela Falco
- Department of Medicine and Surgery, University of Parma
- Birgit Knoechel
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School
- Franco Aversa
- Department of Medicine and Surgery, University of Parma
- Olivia Candini
- Rigenerand S.r.l., Medolla
- Federico Quaini
- Department of Medicine and Surgery, University of Parma
- Paolo Sportoletti
- Department of Medicine, Hematology and Clinical Immunology, University of Perugia
- Kimberly Stegmaier
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School
- Giovanni Roti
- Department of Medicine and Surgery, University of Parma
- DOI
- https://doi.org/10.1038/s41419-022-05002-5
- Journal volume & issue
-
Vol. 13,
no. 6
pp. 1 – 14
Abstract
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.
