DNA methylation of tumor suppressor genes in clinical remission predicts the relapse risk in acute myeloid leukemia.

Abstract

Epigenetic changes play an important role in leukemia pathogenesis. DNA methylation is among the most common alterations in leukemia. The potential role of DNA methylation as a biomarker in leukemia is unknown. In addition, the lack of molecular markers precludes minimal residual disease (MRD) estimation for most patients with hematologic malignancies. We analyzed the potential of aberrant DNA promoter methylation as a biomarker for MRD in acute leukemias. Quantitative real-time PCR methods with bisulfite-modified DNA were established to quantify MRD based on estrogen receptor alpha (ERalpha) and/or p15(INK4B) methylation. Methylation analyses were done in >370 DNA specimens from 180 acute leukemia patients and controls. Methylation of ERalpha and/or p15(INK4B) occurred frequently and specifically in acute leukemia but not in healthy controls or in nonmalignant hematologic diseases. Aberrant DNA methylation was detectable in >20% of leukemia patients during clinical remission. In pediatric acute lymphoblastic leukemia, methylation levels during clinical remission correlated closely with T-cell receptor/immunoglobulin MRD levels (r = +0.7, P < 0.01) and were associated with subsequent relapse. In acute myelogenous leukemia patients in clinical remission, increased methylation levels were associated with a high relapse risk and significantly reduced relapse-free survival (P = 0.003). Many patients with acute leukemia in clinical remission harbor increased levels of aberrant DNA methylation. Analysis of methylation MRD might be used as a novel biomarker for leukemia patients' relapse risk.

• Authors: Shuchi Agrawal, Matthias Unterberg, Steffen Koschmieder, Udo zur Stadt, Uta Brunnberg, Walter Verbeek, Thomas Büchner, Wolfgang E Berdel, Hubert Serve, Carsten Müller-Tidow
• Journal: Cancer research (Cancer Res) Vol. 67 Issue 3 Pg. 1370-7 (Feb 01 2007) ISSN: 0008-5472 [Print] United States
• PMID: 17283175 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cyclin-Dependent Kinase Inhibitor p15
• Estrogen Receptor alpha

Topics

• Acute Disease
• Adolescent
• Child
• Child, Preschool
• Cyclin-Dependent Kinase Inhibitor p15 (genetics, metabolism)
• DNA Methylation
• Estrogen Receptor alpha (genetics, metabolism)
• Female
• Genes, Tumor Suppressor
• Genetic Predisposition to Disease
• Humans
• Leukemia, Myeloid (genetics, metabolism, pathology)
• Male
• Middle Aged
• Neoplasm, Residual
• Polymerase Chain Reaction
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (genetics, metabolism, pathology)
• Risk Factors