title: Synergistic Cytotoxic Effect of L-Asparaginase Combined with Decitabine as a Demethylating Agent in Pediatric T-ALL, with Specific Epigenetic Signature.
abstract: T-Acute Lymphoblastic Leukemia (T-ALL) remains a subgroup of pediatric ALL, with a lower response to standard chemotherapy. Some recent studies established the fundamental role of epigenetic aberrations such as DNA hypermethylation, to influence patients' outcome and response to chemotherapy. Moreover, L-asparaginase is an important chemotherapeutic agent for treatment of ALL and resistance to this drug has been linked toASNSexpression, which can be silenced through methylation. Therefore, we tested whether the sensitivity of T-ALL cell lines towards L-asparaginase is correlated to the epigenetic status ofASNSgene and whether the sensitivity can be modified by concurrent demethylating treatment. Hence we treated different T-ALL cell lines with L-asparaginase and correlated different responses to the treatment withASNSexpression. Then we demonstrated that theASNSexpression was dependent on the methylation status of the promoter. Finally we showed that, despite the demethylating effect on theASNSgene expression, the combined treatment with the demethylating agent Decitabine could synergistically improve the L-asparaginase sensitivity in those T-ALL cell lines characterized by hypermethylation of theASNSgene. In conclusion, this preclinical study identified an unexpected synergistic activity of L-asparaginase and Decitabine in the subgroup of T-ALL with lowASNSexpression due to hypermethylation of theASNSpromoter, while it did not restore sensitivity in the resistant cell lines characterized by higherASNSexpression.
authors.affiliation: Pediatric Hematology and Oncology, Department of Pediatrics, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
authors.forename: Salvatore
authors.identifier: 0000-0003-1304-614X
authors.initials: S
authors.lastname: Serravalle
authors.affiliation: Pediatric Hematology and Oncology, Department of Pediatrics, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
authors.forename: Salvatore N
authors.identifier: 0000-0002-5428-6716
authors.initials: SN
authors.lastname: Bertuccio
authors.affiliation: Pediatric Hematology and Oncology, Department of Pediatrics, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy; "Giorgio Prodi" Cancer Research Center, University of Bologna, Bologna, Italy.
authors.forename: Annalisa
authors.identifier: 0000-0002-2732-0747
authors.initials: A
authors.lastname: Astolfi
authors.affiliation: Pediatric Hematology and Oncology, Department of Pediatrics, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
authors.forename: Fraia
authors.initials: F
authors.lastname: Melchionda
authors.affiliation: Pediatric Hematology and Oncology, Department of Pediatrics, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Pession
mesh_terms: D001216:Asparagine / Q000008:administration & dosage*; D001217:Aspartate-Ammonia Ligase / Q000235:genetics*; D001374:Azacitidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D019175:DNA Methylation / Q000187:drug effects; D000077209:Decitabine; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D044127:Epigenesis, Genetic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D059467:Transcriptome / Q000235:genetics*
chemical_list: D001216:Asparagine; D000077209:Decitabine; D001217:Aspartate-Ammonia Ligase; D001374:Azacitidine