Protein Expression of a Triad of Frequently Methylated Genes, p73, p57Kip2, and p15, Has Prognostic Value in Adult Acute Lymphocytic Leukemia Independently of Its Methylation Status

Abstract

Purpose To study the relationship between protein expression and DNA methylation of a triad of cell-cycle regulatory genes known to be frequently methylated in adult acute lymphocytic leukemia (ALL). Patients and Methods Protein expression of p73, p15, and p57Kip2 was analyzed by immunohistochemistry using a tissue microarray (TMA) platform. The TMA was constructed using pretreatment bone marrow biopsy specimens from 64 adult patients with ALL. Protein expression was then correlated with DNA methylation and relevant clinical biologic characteristics. Results p73 protein expression was observed in 19 (30%) patients, cytoplasmic p15 in 19 (31%), and p57 in 40 (70%). Three patients (5%) had expression of all three proteins, 16 (29%) of two proteins, 31 (55%) of one protein, and six (11%) of zero proteins. An inverse association was observed between p73 DNA methylation and protein expression (P = .003). This effect was not observed for either p15 or p57Kip2. Expression of any of the proteins studied was not associated with any distinct biologic characteristic. By multivariate analysis, expression of p57Kip2, cytoplasmic p15, or a combination of p57Kip2 with either p15 or p73 was associated with a better overall survival (P < .001, .04, and .03 respectively). Conclusion Expression of a triad of cell cycle regulatory proteins that includes p73, p15, and p57Kip2 has prognostic value in adult patients with ALL independently of the methylation status of each gene.