Aberrant DNA methylation ofp57KIP2 gene in the promoter region in lymphoid malignancies of B-cell phenotype

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Abstract
The cyclin-dependent kinase inhibitorp57KIP2 is thought to be a potential tumor suppressor gene (TSG). The present study examines this possibility. We found that the expression ofp57KIP2 gene is absent in various hematological cell lines. Exposing cell lines to the DNA demethylating agent 5-aza-2′-deoxycytidine restoredp57KIP2 gene expression. Bisulfite sequencing analysis of its promoter region showed thatp57KIP2 DNA was completely methylated in cell lines that did not express thep57KIP2 gene. Thus, DNA methylation of its promoter might lead to inactivation of thep57KIP2 gene. DNA methylation of this region is thought to be an aberrant alteration, since DNA was not methylated in normal peripheral blood mononuclear cells or in reactive lymphadenitis. Methylation-specific polymerase chain reaction analysis found frequent DNA methylation of thep57KIP2 gene in primary diffuse large B-cell lymphoma (54.9%) and in follicular lymphoma (44.0%), but methylation was infrequent in myelodysplastic syndrome and adult T-cell leukemia (3.0% and 2.0%, respectively). These findings directly indicate that the profile of the p57KIP2gene corresponds to that of a TSG.