Aberrant DNA methylation of p57KIP2 identifies a cell-cycle regulatory pathway with prognostic impact in adult acute lymphocytic leukemia.
P57KIP2 is a cyclin-dependent kinase inhibitor silenced in a variety of human malignancies. DNA methylation of a region surrounding the transcription start site of p57KIP2 was found in acute lymphocytic leukemia (ALL)-derived cell lines. Methylation of this region correlated with gene silencing, and treatment of methylated/silenced cell lines with 5-aza-2'-deoxycytidine resulted in gene re-expression. P57KIP2 was methylated in 31 (50%) of 63 patients with newly diagnosed ALL, and in 11 (52%) of 21 patients with relapsed ALL. In 5 of them (25%), methylation was acquired at relapse. No association was observed between methylation of p57KIP2 alone and clinical-biologic characteristics studied, including overall survival (OS) or disease-free survival. Methylation of multiple genes in a cell-cycle regulatory pathway composed of p73, p15, and p57KIP2 occurred in 22% of Philadelphia chromosome (Ph)-negative patients. Ph-negative patients with methylation of 2 or 3 genes of this pathway had a significantly worse median OS compared with those with methylation of 0 or 1 gene (50 vs 467 weeks, respectively; P =.02). Our results indicate that p57KIP2 is frequently methylated in adult patients with ALL, and that inactivation of a pathway composed of p73, p15, and p57KIP2 predicts for poor prognosis in Ph-negative patients.
Shen
LanLan
L
Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Toyota
Minoru
M
Kondo
Yutaka
Y
Obata
Toshiro
T
Daniel
Sophia
S
Pierce
Sherry
S
Imai
Kohzoh
K
Kantarjian
Hagop M
HM
Issa
Jean-Pierre J
JP
Garcia-Manero
Guillermo
G
D000293:Adolescent; D000328:Adult; D000368:Aged; D002453:Cell Cycle / Q000502:physiology*; D050761:Cyclin-Dependent Kinase Inhibitor p57; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D019175:DNA Methylation; D004791:Enzyme Inhibitors / Q000378:metabolism; D005260:Female; D006801:Humans; D019169:Jurkat Cells; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000097:blood / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000378:metabolism*; D011379:Prognosis; D016019:Survival Analysis; D013997:Time Factors; D014407:Tumor Cells, Cultured
C493964:CDKN1C protein, human; D050761:Cyclin-Dependent Kinase Inhibitor p57; D004791:Enzyme Inhibitors; D009687:Nuclear Proteins; D018844:Cyclin-Dependent Kinases