TY - JOUR
T1 - Aberrant DNA methylation of p57KIP2 identifies a cell-cycle regulatory pathway with prognostic impact in adult acute lymphocytic leukemia
AU - Shen, Lan Lan
AU - Toyota, Minoru
AU - Kondo, Yutaka
AU - Obata, Toshiro
AU - Daniel, Sophia
AU - Pierce, Sherry
AU - Imai, Kohzoh
AU - Kantarjian, Hagop M.
AU - Issa, Jean Pierre J.
AU - Garcia-Manero, Guillermo
PY - 2003/5/15
Y1 - 2003/5/15
N2 - 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.
AB - 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.
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U2 - 10.1182/blood-2002-08-2466
DO - 10.1182/blood-2002-08-2466
M3 - Article
C2 - 12586619
AN - SCOPUS:0037625237
SN - 0006-4971
VL - 101
SP - 4131
EP - 4136
JO - Blood
JF - Blood
IS - 10
ER -