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.

Identification of an Epi-metabolic dependency on EHMT2/G9a in T-cell acute lymphoblastic leukemia / Montanaro, Anna; Kitara, Samuel; Cerretani, Elisa; Marchesini, Matteo; Rompietti, Chiara; Pagliaro, Luca; Gherli, Andrea; Su, Angela; Minchillo, Maria Laura; Caputi, Maria francesca; Fioretzaki, Rodanthi; Lorusso, Bruno; Ross, Linda; Alexe, Gabriela; Masselli, Elena; Marozzi, Marina; Rizzi, Federica Maria Angela; La Starza, Roberta; Mecucci, Cristina; Xiong, Yan; Jin, Jian; Falco, Angela; Knoechel, Birgit; Aversa, Franco; Candini, Olivia; Quaini, Federico; Sportoletti, Paolo; Stegmaier, Kimberly; Roti, Giovanni. - In: CELL DEATH & DISEASE. - ISSN 2041-4889. - 13:6(2022), p. 551. [10.1038/s41419-022-05002-5]

Identification of an Epi-metabolic dependency on EHMT2/G9a in T-cell acute lymphoblastic leukemia

Montanaro, Anna;Cerretani, Elisa;Marchesini, Matteo;Pagliaro, Luca;Gherli, Andrea;Fioretzaki, Rodanthi;Lorusso, Bruno;Masselli, Elena;Marozzi, Marina;Rizzi, Federica Maria Angela;Mecucci, Cristina;Falco, Angela;Aversa, Franco;Quaini, Federico;Roti, Giovanni
2022-01-01

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.
2022
Identification of an Epi-metabolic dependency on EHMT2/G9a in T-cell acute lymphoblastic leukemia / Montanaro, Anna; Kitara, Samuel; Cerretani, Elisa; Marchesini, Matteo; Rompietti, Chiara; Pagliaro, Luca; Gherli, Andrea; Su, Angela; Minchillo, Maria Laura; Caputi, Maria francesca; Fioretzaki, Rodanthi; Lorusso, Bruno; Ross, Linda; Alexe, Gabriela; Masselli, Elena; Marozzi, Marina; Rizzi, Federica Maria Angela; La Starza, Roberta; Mecucci, Cristina; Xiong, Yan; Jin, Jian; Falco, Angela; Knoechel, Birgit; Aversa, Franco; Candini, Olivia; Quaini, Federico; Sportoletti, Paolo; Stegmaier, Kimberly; Roti, Giovanni. - In: CELL DEATH & DISEASE. - ISSN 2041-4889. - 13:6(2022), p. 551. [10.1038/s41419-022-05002-5]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11381/2934117
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