title: Epigenetic reprogramming reverses the relapse-specific gene expression signature and restores chemosensitivity in childhood B-lymphoblastic leukemia.
abstract: Whereas the improvement in outcome for children with acute lymphoblastic leukemia has been gratifying, the poor outcome of patients who relapse warrants novel treatment approaches. Previously, we identified a characteristic relapse-specific gene expression and methylation signature associated with chemoresistance using a large cohort of matched-diagnosis relapse samples. We hypothesized that "reversing" such a signature might restore chemosensitivity. In the present study, we demonstrate that the histone deacetylase inhibitor vorinostat not only reprograms the aberrant gene expression profile of relapsed blasts by epigenetic mechanisms, but is also synergistic when applied before chemotherapy in primary patient samples and leukemia cell lines. Furthermore, incorporation of the DNA methyltransferase inhibitor decitabine led to reexpression of genes shown to be preferentially methylated and silenced at relapse. Combination pretreatment with vorinostat and decitabine resulted in even greater cytotoxicity compared with each agent individually with chemotherapy. Our results indicate that acquisition of chemo-resistance at relapse may be driven in part by epigenetic mechanisms. Incorporation of these targeted epigenetic agents to the standard chemotherapy backbone is a promising approach to the treatment of relapsed pediatric acute lymphoblastic leukemia.
authors.affiliation: New York University Cancer Institute, New York University Langone Medical Center, New York, NY 10016, USA.
authors.forename: Teena
authors.initials: T
authors.lastname: Bhatla
authors.forename: Jinhua
authors.initials: J
authors.lastname: Wang
authors.forename: Debra J
authors.initials: DJ
authors.lastname: Morrison
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Raetz
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Burke
authors.forename: Patrick
authors.initials: P
authors.lastname: Brown
authors.forename: William L
authors.initials: WL
authors.lastname: Carroll
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D001752:Blast Crisis / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D019175:DNA Methylation / Q000187:drug effects*; D000077209:Decitabine; D005260:Female; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects*; D020868:Gene Silencing / Q000187:drug effects*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology / Q000627:therapeutic use; D015448:Leukemia, B-Cell / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D000077337:Vorinostat
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D000077337:Vorinostat; D000077209:Decitabine; D001374:Azacitidine