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STAT5A regulates DNMT3A in CD34(+)/CD38(-) AML cells

Asako Takeuchi1, Chie Nishioka1, Takayuki Ikezoe1

  • 1Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi University, Okoh-cho, Nankoku 783-8505, Kochi, Japan.

Leukemia Research
|June 11, 2015
PubMed

Insights

Signal transducer and activator of transcription 5 (STAT5) activates DNA methyltransferase 3A (DNMT3A) in acute myelogenous leukemia (AML) cells. This STAT5-DNMT3A pathway epigenetically silences tumor suppressor genes, offering new therapeutic targets for AML.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Epigenetics

Background:

  • Signal transducer and activator of transcription 5 (STAT5) is constitutively active in CD34(+)/CD38(-) acute myelogenous leukemia (AML) cells.
  • STAT5 inhibition induces apoptosis and enhances sensitivity to chemotherapy in AML cells.
  • Understanding STAT5-regulated genes is crucial for developing novel AML therapies.

Purpose of the Study:

  • To identify molecules regulated by STAT5 in CD34(+)/CD38(-) AML cells.
  • To elucidate the role of STAT5 in regulating DNA methyltransferase 3A (DNMT3A) expression and activity.
  • To investigate the impact of STAT5-mediated DNMT3A regulation on tumor suppressor gene methylation and expression.

Main Methods:

  • cDNA microarrays to compare gene expression profiles between control and STAT5A-depleted AML cells.
  • Reporter gene assays to assess DNMT3A transcriptional activity in response to STAT5 activation/inhibition.
  • Chromatin immunoprecipitation (ChIP) assays to identify STAT5A-binding sites on the DNMT3A promoter.
  • Methylation-specific and real-time quantitative PCR to analyze PTEN promoter methylation and mRNA levels.

Main Results:

  • DNA methyltransferase 3A (DNMT3A) was significantly downregulated upon STAT5A depletion in AML cells.
  • STAT5A activation increased DNMT3A activity, while its dephosphorylation by AZ960 decreased it.
  • A direct STAT5A-binding site was identified on the DNMT3A promoter region.
  • Forced STAT5A expression led to hypermethylation of the PTEN tumor suppressor gene promoter and reduced PTEN mRNA levels.

Conclusions:

  • STAT5A positively regulates DNMT3A levels in AML cells.
  • STAT5A-driven DNMT3A promotes epigenetic silencing of tumor suppressor genes like PTEN in AML.
  • Targeting the STAT5A-DNMT3A axis represents a potential therapeutic strategy for AML.
Keywords:
AMLDNMT3APTENSTAT5A

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