Aberrant DNA methylation of p57(KIP2) gene in the promoter region in lymphoid malignancies of B-cell phenotype.

The cyclin-dependent kinase inhibitor p57KIP2 is thought to be a potential tumor suppressor gene (TSG). The present study examines this possibility. We found that the expression of p57KIP2 gene is absent in various hematological cell lines. Exposing cell lines to the DNA demethylating agent 5-aza-2′-deoxycytidine restored p57KIP2 gene expression. Bisulfite sequencing analysis of its promoter region showed that p57KIP2 DNA was completely methylated in cell lines that did not express the p57KIP2 gene. Thus, DNA methylation of its promoter might lead to inactivation of the p57KIP2 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 the p57KIP2 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 p57KIP2 gene corresponds to that of a TSG.