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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

04/13/2012

Pubmed ID

22496163

Pubmed Central ID

PMC3369610

DOI

10.1182/blood-2012-01-401687

Scopus ID

2-s2.0-84861904198   88 Citations

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.

Author List

Bhatla T, Wang J, Morrison DJ, Raetz EA, Burke MJ, Brown P, Carroll WL

Author

Michael James Burke MD Professor in the Pediatrics department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Antineoplastic Combined Chemotherapy Protocols
Azacitidine
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
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a