Epigenetic reprogramming reverses the relapse-specific gene expression signature and restores chemosensitivity in childhood B-lymphoblastic leukemia

Teena Bhatla, Jinhua Wang, Debra J. Morrison, Elizabeth A. Raetz, Michael J. Burke, Patrick A Brown, William L. Carroll

Research output: Contribution to journalArticle

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 chemoresistance 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.

Original languageEnglish (US)
Pages (from-to)5201-5210
Number of pages10
JournalBlood
Volume119
Issue number22
DOIs
StatePublished - Jun 5 2012

Fingerprint

decitabine
Chemotherapy
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Transcriptome
Epigenomics
Gene expression
Recurrence
Pediatrics
Histone Deacetylase Inhibitors
Methylation
Drug Therapy
Methyltransferases
Cytotoxicity
Genes
Cells
DNA
Leukemia
Cell Line
Therapeutics
vorinostat

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

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Epigenetic reprogramming reverses the relapse-specific gene expression signature and restores chemosensitivity in childhood B-lymphoblastic leukemia. / Bhatla, Teena; Wang, Jinhua; Morrison, Debra J.; Raetz, Elizabeth A.; Burke, Michael J.; Brown, Patrick A; Carroll, William L.

In: Blood, Vol. 119, No. 22, 05.06.2012, p. 5201-5210.

Research output: Contribution to journalArticle

Bhatla, Teena ; Wang, Jinhua ; Morrison, Debra J. ; Raetz, Elizabeth A. ; Burke, Michael J. ; Brown, Patrick A ; Carroll, William L. / Epigenetic reprogramming reverses the relapse-specific gene expression signature and restores chemosensitivity in childhood B-lymphoblastic leukemia. In: Blood. 2012 ; Vol. 119, No. 22. pp. 5201-5210.
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