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Methylation status of cyclin-dependent kinase inhibitor genes within the transforming growth factor beta pathway in

Stuart A Scott1, Tomofumi Kimura, Wei-Feng Dong

  • 1Department of Pathology, Saskatoon Cancer Centre, Royal University Hospital, University of Saskatchewan, 103 Hospital Drive, Saskatoon, Saskatchewan, S7N 0W8, Canada.

Leukemia Research
|October 12, 2004
PubMed

Insights

Epigenetic silencing of cyclin-dependent kinase inhibitors (CDKIs) is key in hematological malignancies. This study shows p21CIP1 loss in T-cell acute lymphoblastic leukemia (T-ALL) is not due to promoter methylation, unlike p15INK4B.

Area of Science:

  • Molecular Biology
  • Oncology
  • Epigenetics

Background:

  • Epigenetic silencing of cyclin-dependent kinase inhibitors (CDKIs) contributes to hematological malignancies.
  • p15INK4B promoter methylation is frequent in T-cell acute lymphoblastic leukemia (T-ALL).
  • The role of p27KIP1 and p21CIP1 methylation in T-ALL and T-cell lymphoblastic lymphoma (T-LBL) requires further investigation.

Purpose of the Study:

  • To investigate the expression and methylation status of p27KIP1 and p21CIP1 in T-LBL and T-ALL.
  • To determine the relationship between p21CIP1 expression and promoter methylation in T-LBL.

Main Methods:

  • RNase protection assays (RPA) were used to assess gene expression.
  • Methylation-specific PCR (MSP) and temporal temperature gradient electrophoresis (TTGE) were employed to analyze promoter methylation.
  • Analysis was conducted on T-LBL biopsies and T-ALL cell lines.

Main Results:

  • p27KIP1 was expressed and its promoter unmethylated in all T-LBL/ALL samples analyzed.
  • p21CIP1 mRNA was frequently absent in T-LBL biopsies (50%) and T-ALL cell lines (83%).
  • Despite frequent loss of expression, p21CIP1 promoter methylation was not detected in T-LBL/ALL samples; p15INK4B promoter methylation was observed in 64% of T-LBL cases.

Conclusions:

  • Reduced p21CIP1 expression in T-LBL/ALL is frequent and independent of promoter methylation.
  • Unlike p15INK4B, p21CIP1 promoter methylation does not appear to be a major mechanism driving its silencing in T-LBL/ALL.
  • p27KIP1 methylation is unlikely to be a significant factor in T-LBL/ALL pathogenesis.

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