Aberrant DNA methylation of p57KIP2 identifies a cell-cycle regulatory pathway with prognostic impact in adult acute lymphocytic leukemia

Abstract

P57KIP2 is a cyclin-dependent kinase inhibitor silenced in a variety of human malignancies. DNA methylation of a region surrounding the transcription start site of p57KIP2 was found in acute lymphocytic leukemia (ALL)-derived cell lines. Methylation of this region correlated with gene silencing, and treatment of methylated/silenced cell lines with 5-aza-2'-deoxycytidine resulted in gene re-expression. P57KIP2 was methylated in 31 (50%) of 63 patients with newly diagnosed ALL, and in 11 (52%) of 21 patients with relapsed ALL. In 5 of them (25%), methylation was acquired at relapse. No association was observed between methylation of p57KIP2 alone and clinical-biologic characteristics studied, including overall survival (OS) or disease-free survival. Methylation of multiple genes in a cell-cycle regulatory pathway composed of p73, p15, and p57KIP2 occurred in 22% of Philadelphia chromosome (Ph)-negative patients. Ph-negative patients with methylation of 2 or 3 genes of this pathway had a significantly worse median OS compared with those with methylation of 0 or 1 gene (50 vs 467 weeks, respectively; P =.02). Our results indicate that p57KIP2 is frequently methylated in adult patients with ALL, and that inactivation of a pathway composed of p73, p15, and p57KIP2 predicts for poor prognosis in Ph-negative patients.