Originally published as JCO Early Release 10.1200/JCO.2005.02.998 on April 25 2005

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Protein Expression of a Triad of Frequently Methylated Genes, p73, p57^Kip2, and p15, Has Prognostic Value in Adult Acute Lymphocytic Leukemia Independently of Its Methylation Status

Carlos Bueso-Ramos, Yunling Xu, Timothy J. McDonnell, Shawn Brisbay, Sherry Pierce, Hagop Kantarjian, Gary Rosner, Guillermo Garcia-Manero

From the Departments of Hematopathology, Biostatistics and Applied Mathematics, Molecular Pathology, and Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX

Address reprint requests to Guillermo Garcia-Manero, MD, Department of Leukemia, Box 428, The University of Texas M.D. Anderson Cancer Center, PO Box 301402, Houston, TX 77230-1402; e-mail: ggarciam{at}mdanderson.org.

PURPOSE: To study the relationship between protein expression and DNA methylation of a triad of cell-cycle regulatory genes known to be frequently methylated in adult acute lymphocytic leukemia (ALL).

PATIENTS AND METHODS: Protein expression of p73, p15, and p57^Kip2 was analyzed by immunohistochemistry using a tissue microarray (TMA) platform. The TMA was constructed using pretreatment bone marrow biopsy specimens from 64 adult patients with ALL. Protein expression was then correlated with DNA methylation and relevant clinical biologic characteristics.

RESULTS: p73 protein expression was observed in 19 (30%) patients, cytoplasmic p15 in 19 (31%), and p57 in 40 (70%). Three patients (5%) had expression of all three proteins, 16 (29%) of two proteins, 31 (55%) of one protein, and six (11%) of zero proteins. An inverse association was observed between p73 DNA methylation and protein expression (P = .003). This effect was not observed for either p15 or p57^Kip2. Expression of any of the proteins studied was not associated with any distinct biologic characteristic. By multivariate analysis, expression of p57^Kip2, cytoplasmic p15, or a combination of p57^Kip2 with either p15 or p73 was associated with a better overall survival (P < .001, .04, and .03 respectively).

CONCLUSION: Expression of a triad of cell cycle regulatory proteins that includes p73, p15, and p57^Kip2 has prognostic value in adult patients with ALL independently of the methylation status of each gene.

Funded in part by a Career Development Award from the American Society of Clinical Oncology, the Physician-Scientist Award from The University of Texas M.D. Anderson Cancer Center, and grants CA105771 and CA100067 from the National Institutes of Health (G.G-M.).

Terms in blue are defined in the glossary, found at the end of this issue and online at www.jco.org.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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