Epigenetic reprogramming reverses the relapse-specific gene expression signature and restores chemosensitivity in childhood B-lymphoblastic leukemia. Blood 2012 May 31;119(22):5201-10
Date
04/13/2012Pubmed ID
22496163Pubmed Central ID
PMC3369610DOI
10.1182/blood-2012-01-401687Scopus ID
2-s2.0-84861904198 (requires institutional sign-in at Scopus site) 117 CitationsAbstract
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.
Author List
Bhatla T, Wang J, Morrison DJ, Raetz EA, Burke MJ, Brown P, Carroll WLAuthor
Michael James Burke MD Professor in the Pediatrics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Antineoplastic Combined Chemotherapy ProtocolsAzacitidine
Blast Crisis
Cell Line, Tumor
Child
Child, Preschool
Cohort Studies
DNA Methylation
Female
Gene Expression Regulation, Leukemic
Gene Silencing
Histone Deacetylase Inhibitors
Humans
Hydroxamic Acids
Leukemia, B-Cell
Male
