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Prepublished online as a Blood First Edition Paper on February 13, 2003; DOI 10.1182/blood-2002-08-2466.
Submitted August 12, 2002
Accepted January 14, 2003
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*
Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA
First Department of Internal Medicine and Department of Molecular Biology, Sapporo Medical University, Sapporo, Japan
* Corresponding author; email: ggarciam{at}mdanderson.org.
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 reexpression. P57KIP2 was methylated in 31 out of 63 patients (50%) with newly diagnosed ALL, and in 11 of 21 (52%) 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-biological 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 (Ph) chromosome 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, p=0.02). 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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