Frequent DAP kinase but not p14 or Apaf-1 hypermethylation in B-cell chronic lymphocytic leukemia

Abstract

Dysregulation of apoptosis, and thus the p14/DAP kinase/HDM2/p53/Apaf-1 pathway, is potentially important in carcinogenesis. Chronic lymphocytic leukemia (CLL), uncommon in the Chinese, is a disease characterized by impaired apoptosis, of the neoplastic lymphocytes. Hypermethylation of p14, DAP kinase and Apaf-1 was studied by methylation-specific polymerase chain reaction (MSP) with primers for methylated (M-MSP) and unmethylated (U-MSP) alleles in 50 diagnostic marrow samples from patients with CLL. Chinese CLL patients had an indolent course similar to Caucasians with median overall survival (OS) of 96 months, which was adversely affected by advanced Rai stage (projected 5-year OS = 72% and 39% for Rai < or = 2 and Rai > 2; P = 0.01). DAP kinase was methylated in 18 (36%) patients while p14 and Apaf-1 were completely unmethylated in all the primary CLL samples. There was no correlation between DAP kinase hypermethylation and age, sex, poor-risk karyotype, lymphocyte count and Rai stage at diagnosis. Projected OS for patients with and without DAP kinase hypermethylation were 59 and 57% (P = 0.91). DAP kinase, but not p14 and Apaf-1, of the DAP kinase/p14/HDM2/p53/Apaf-1 pathway is frequently hypermethylated in CLL, but not of prognostic significance. Moreover Chinese patients with CLL share a similarly indolent clinical course, and this is the first comprehensive study on p14, DAP kinase and Apaf-1 hypermethylation in CLL.