title: 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.
authors.affiliation: University Department of Medicine, Queen Mary Hospital, University of Hong Kong, Pokfulam Road, Hong Kong, China. jcschim@hku.hk.
authors.forename: C S
authors.initials: CS
authors.lastname: Chim
authors.affiliation: University Department of Medicine, Queen Mary Hospital, University of Hong Kong, Pokfulam Road, Hong Kong, China.
authors.forename: T K
authors.initials: TK
authors.lastname: Fung
authors.affiliation: Department of Pathology, Queen Elizabeth Hospital, Hong Kong, China.
authors.forename: K F
authors.initials: KF
authors.lastname: Wong
authors.affiliation: Department of Medicine, Queen Elizabeth Hospital, Hong Kong, China.
authors.forename: J S
authors.initials: JS
authors.lastname: Lau
authors.affiliation: University Department of Medicine, Queen Mary Hospital, University of Hong Kong, Pokfulam Road, Hong Kong, China.
authors.forename: R
authors.initials: R
authors.lastname: Liang
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D053477:Apoptotic Protease-Activating Factor 1; D044466:Asian People / Q000235:genetics; D001483:Base Sequence; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics*; D016022:Case-Control Studies; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000737:chemistry / Q000235:genetics; D064550:Death-Associated Protein Kinases; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D011506:Proteins / Q000235:genetics; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics
chemical_list: C506592:APAF1 protein, human; D051017:Apoptosis Regulatory Proteins; D053477:Apoptotic Protease-Activating Factor 1; D004273:DNA, Neoplasm; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; D025803:Tumor Suppressor Protein p14ARF; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases