P53-inducible ribonucleotide reductase (P53R2/RRM2B) is a DNA hypomethylation-independent decitabine gene target that correlates with clinical response in myelodysplastic syndrome/acute myelogenous leukemia

Petra A. Link, Maria R. Baer, Smitha R. James, David A. Jones, Adam R. Karpf

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

While the therapeutic activity of the deoxycytidine analogue decitabine is thought to reflect its ability to reactivate methylation-silenced genes, this agent is also known to trigger p53-dependent DNA damage responses.Her e, we report that p53-inducible ribonucleotide reductase (p53R2/RRM2B) is a robust transcriptional target of decitabine.In cancer cells, decitabine treatment induces p53R2 mRNA expression, protein expression, and promoter activity in a p53-dependent manner.T he mechanism of p53R2 gene induction by decitabine does not seem to be promoter DNA hypomethylation, as the p53R2 5′ CpG island is hypomethylated before treatment.Small interfering RNA (siRNA) targeting of DNA methyltransferase 1 (DNMT1) in wild-type p53 cells leads to genomic DNA hypomethylation but does not induce p53R2, suggesting that DNMT/DNA adduct formation is the molecular trigger for p53R2 induction.Consis tent with this idea, only nucleoside-based DNMT inhibitors that form covalent DNA adducts induce p53R2 expression.siR NA targeting of p53R2 reduces the extent of cell cycle arrest following decitabine treatment, supporting a functional role for p53R2 in decitabine-mediated cellular responses.T o determine the clinical relevance of p53R2 induction, we measured p53R2 expression in bone marrow samples from 15 myelodysplastic syndrome/ acute myelogenous leukemia (MDS/AML) patients undergoing decitabine therapy.p53R2 mRNA and protein were induced in 7 of 13 (54%) and 6 of 9 (67%) patients analyzed, respectively, despite a lack of methylation changes in the p53R2 promoter. Most notably, there was a significant association (P = 0.0047) between p53R2 mRNA induction and clinical response in MDS/AML.These data establish p53R2 as a novel hypomethylation-independent decitabine gene target associated with clinical response.

Original languageEnglish (US)
Pages (from-to)9358-9366
Number of pages9
JournalCancer Research
Volume68
Issue number22
DOIs
StatePublished - Nov 15 2008

Fingerprint

decitabine
Ribonucleotide Reductases
Myelodysplastic Syndromes
Acute Myeloid Leukemia
DNA
Genes
DNA Adducts
Messenger RNA
Methylation
Therapeutics
Deoxycytidine
CpG Islands
Methyltransferases
Cell Cycle Checkpoints
Nucleosides
Small Interfering RNA
DNA Damage

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

P53-inducible ribonucleotide reductase (P53R2/RRM2B) is a DNA hypomethylation-independent decitabine gene target that correlates with clinical response in myelodysplastic syndrome/acute myelogenous leukemia. / Link, Petra A.; Baer, Maria R.; James, Smitha R.; Jones, David A.; Karpf, Adam R.

In: Cancer Research, Vol. 68, No. 22, 15.11.2008, p. 9358-9366.

Research output: Contribution to journalArticle

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abstract = "While the therapeutic activity of the deoxycytidine analogue decitabine is thought to reflect its ability to reactivate methylation-silenced genes, this agent is also known to trigger p53-dependent DNA damage responses.Her e, we report that p53-inducible ribonucleotide reductase (p53R2/RRM2B) is a robust transcriptional target of decitabine.In cancer cells, decitabine treatment induces p53R2 mRNA expression, protein expression, and promoter activity in a p53-dependent manner.T he mechanism of p53R2 gene induction by decitabine does not seem to be promoter DNA hypomethylation, as the p53R2 5′ CpG island is hypomethylated before treatment.Small interfering RNA (siRNA) targeting of DNA methyltransferase 1 (DNMT1) in wild-type p53 cells leads to genomic DNA hypomethylation but does not induce p53R2, suggesting that DNMT/DNA adduct formation is the molecular trigger for p53R2 induction.Consis tent with this idea, only nucleoside-based DNMT inhibitors that form covalent DNA adducts induce p53R2 expression.siR NA targeting of p53R2 reduces the extent of cell cycle arrest following decitabine treatment, supporting a functional role for p53R2 in decitabine-mediated cellular responses.T o determine the clinical relevance of p53R2 induction, we measured p53R2 expression in bone marrow samples from 15 myelodysplastic syndrome/ acute myelogenous leukemia (MDS/AML) patients undergoing decitabine therapy.p53R2 mRNA and protein were induced in 7 of 13 (54{\%}) and 6 of 9 (67{\%}) patients analyzed, respectively, despite a lack of methylation changes in the p53R2 promoter. Most notably, there was a significant association (P = 0.0047) between p53R2 mRNA induction and clinical response in MDS/AML.These data establish p53R2 as a novel hypomethylation-independent decitabine gene target associated with clinical response.",
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