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Prepublished online as a Blood First Edition Paper on February 13, 2003; DOI 10.1182/blood-2002-08-2466.
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Blood, 15 May 2003, Vol. 101, No. 10, pp. 4131-4136
NEOPLASIA
Aberrant DNA methylation of p57KIP2 identifies a cell-cycle
regulatory pathway with prognostic impact in adult acute lymphocytic
leukemia
LanLan Shen,
Minoru Toyota,
Yutaka Kondo,
Toshiro Obata,
Sophia Daniel,
Sherry Pierce,
Kohzoh Imai,
Hagop M. Kantarjian,
Jean-Pierre J. Issa, and
Guillermo Garcia-Manero
From the Department of Leukemia, University of Texas
M.D. Anderson Cancer Center, Houston, TX; and the First Department of
Internal Medicine and the Department of Molecular Biology, Cancer
Research Institute, Sapporo Medical University, Sapporo,
Japan.
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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