Methylation of INK4 and CIP/KIP families of cyclin-dependent kinase inhibitor in chronic lymphocytic leukaemia in Chinese patients.
BACKGROUND
INK4 (p15, p16, p18 and p19) and CIP/KIP (p21, p27 and p57) are two families of cyclin-dependent kinase inhibitors (CKI) targeting CDK4/6 and CDK2, respectively.


OBJECTIVE
To study the role of methylation in the inactivation of CKI in chronic lymphocytic leukaemia (CLL).


METHODS
Methylation-specific polymerase chain reaction was carried out on DNA obtained from the bone marrow of 56 newly diagnosed patients with CLL.


RESULTS
Similar demographic features and clinical outcome were observed in our patients when compared with Caucasian patients, including an indolent clinical course (10-year overall survival 51%) and advanced Rai stage (p = 0.006), and a high-risk karyotype such as trisomy 12 and complex aberrations (p = 0.03). In the INK4 family, methylation in p15 and p16 occurred in 20 (35.7%) and 8 (14.3%) patients, respectively. In all, 5 (8.9%) CLL samples harboured concurrent methylation of both p15 and p16. Apart from an association of p16 methylation with higher presenting leucocyte count (64.5 x 10(9)/l in methylated p16 and 16.0 x 10(9)/l in unmethylated p16 patients; p = 0.016), there was no association between p15 and p16 methylation and age, sex and Rai stage. No difference was observed in the overall survival for patients with and without p15 and p16 methylation. By contrast, p18 and Rb were unmethylated in all samples. In the CIP/KIP family, apart from infrequent methylation of p57 in 4 (7.1%) patients, methylation of p21 and p27 was uniformly absent.


CONCLUSIONS
p15 and, less frequently, p16 of the INK4 family of CKI, instead of the CIP or KIP family, were targeted by methylation in CLL. p16 methylation was associated with a higher lymphocyte count at presentation. This is the first comprehensive study of the epigenetic dysregulation of the INK4 and CIP/KIP families of CKI in Chinese patients with CLL.
Department of Medicine, Queen Mary Hospital, Hong Kong. jcshim@hku.hk
C S
CS
Chim
T K
TK
Fung
K F
KF
Wong
J S
JS
Lau
M
M
Law
R
R
Liang
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000235:genetics*; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics*; D044127:Epigenesis, Genetic; D005260:Female; D006801:Humans; D007621:Karyotyping; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics*; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000235:genetics; D016133:Polymerase Chain Reaction / Q000379:methods; D011379:Prognosis; D016019:Survival Analysis
D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004273:DNA, Neoplasm; D009363:Neoplasm Proteins