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 methylationspecific 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 £ 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.

DNA Hypermethylation of Cell Cycle (p15 and p16) and Apoptotic (p14, p53, DAPK and TMS1) Genes in Peripheral Blood of Leukemia Patients

“…Methylation of DAPK was seen in 36% of CLL patients in this study. Two previous reports showed methylation in 9% (n=11) (katzenllenbogen et al, 1999) and 36% (n=50) (Chim et al, 2006b). Furthermore, none of the ALL patients showed methylation of DAPK gene, which was in accordance with Matsushita et al (2004) and Yang et al (2006).…”

“…In CLL patients, methylation was reported in p15 (Nguyen et al, 2001;Chim et al, 2006;Seeliger et al, 2009), p16 (Nosaka et al, 2000;Chim et al, 2006a;Tsirigotis et al, 2006;Seeliger et al, 2009) and DAPK (Katzenellenbogen et al, 1999;Chim et al, 2006b).…”

Methylation of miR124a-1, miR124a-2, and miR124a-3 in Hodgkin lymphoma

“…Multiple tumor suppressor genes have been shown to be inactivated by promoter hypermethylation in leukemia, lymphomas, and multiple myeloma [5][6][7][8][9][10][11][12][13]. The same mechanism has been also implicated in the loss of microRNA (miRNA) expression in tumors.…”

A Novel Recombinant Anti-CD22 Immunokinase Delivers Proapoptotic Activity of Death-Associated Protein Kinase (DAPK) and Mediates Cytotoxicity in Neoplastic B Cells

“…6,16). In addition, a CLL haplotype with allele-specific imbalances of DAPK1 expression indicates that recurring germline single-nucleotide variants and promoter methylation can be considered as predisposing to (familial) CLL (16,17).…”

“…They share a 50% to 80% homology of their catalytic domains. Loss-of-function of the DAPK tumor suppressors is implicated as a central tumor-initiating and metastasis -promoting event in a broad range of cancers, that is, of breast, lung, head and neck, gastrointestinal, and the hematopoetic system (1,5,6). The causes of tumor-associated DAPK deficiency are primarily epigenetic mechanisms (promoter hypermethylation), but also genomic deletions with subsequent LOH are observed (1,7,8).…”