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Inactivation of the p16 Cyclin-Dependent Kinase Inhibitor in High-Grade Canine Non-Hodgkin's T-Cell Lymphoma

Integrated Department of Immunology (SPF, CMJ, LAG, JFM) and University of Colorado Cancer Center (SPF, CMJ, TLS, LAG, JFM), University of Colorado at Denver and Health Sciences Center, School of Medicine, Denver, CO; Department of Molecular Biomedical Sciences (RT, MB), North Carolina State University, College of Veterinary Medicine, Raleigh, NC, IHC Services (JWW), Smithville, TX, Department of Pathobiology (VEOV), University of Illinois, College of Veterinary Medicine, Urbana, IL, Idexx Veterinary Services (DMG), Broomfield, CO, Animal Hospital Center (MGR), Highlands Ranch, CO, Department of Clinical Sciences (JSB), Tufts Cummings School of Veterinary Medicine, North Grafton, MA, Northwest Veterinary Specialists (KPF), Clackamas, OR, Animal Clinic Northview (BEG), North Ridgeville, OH, Department of Clinical Sciences and Animal Cancer Center (SEL), Colorado State University, College of Veterinary Medicine and Biomedical Sciences, Fort Collins, CO, Department of Veterinary Clinical Sciences (WCK), The Ohio State University College of Veterinary Medicine, Columbus, OH, Oregon Regional Cancer Center for Animals (SCH), Oregon State University, Corvallis, OR, Department of Biostatistics (GRC), University of Alabama at Birmingham, Birmingham, AL, Center for Comparative Medicine and Translational Research (MB), North Carolina State University, Raleigh, NC

The significance of p16/Rb tumor suppressor pathway inactivation in T-cell non-Hodgkin's lymphoma (NHL) remains incompletely understood. We used naturally occurring canine NHL to test the hypothesis that p16 inactivation has specific pathologic correlates. Forty-eight samples (22 T-cell NHL and 26 B-cell NHL) were included. As applicable, metaphase- or array-based comparative genomic hybridization, Southern blotting, promoter methylation, and Rb phosphorylation were used to determine the presence, expression, and activity of p16. Fisher's exact test was used to test for significance. Deletion of p16 (or loss of dog chromosome 11) was restricted to high-grade T-cell NHL (lymphoblastic T-cell lymphoma and peripheral T-cell lymphoma, not otherwise specified). These were characterized by a concomitant increase of tumor cells with Rb phosphorylation at canonical CDK4 sites. Rb phosphorylation also was seen in high-grade B-cell NHL (diffuse large B-cell lymphoma and Burkitt-type lymphoma), but in those cases, it appeared to be associated with c-Myc overexpression. The data show that p16 deletion or inactivation occurs almost exclusively in high-grade T-cell NHL; however, alternative pathways can generate functional phenotypes of Rb deficiency in low-grade T-cell NHL and in high-grade B-cell NHL. Both morphologic classification according to World Health Organization criteria and assessment of Rb phosphorylation are prognostically valuable parameters for canine NHL.

Key words: Canines; cell cycle; non-Hodgkin's lymphoma; tumor suppressor genes.

Request reprints from Dr. Jaime F. Modiano, Integrated Department of Immunology, University of Colorado at Denver and Health Sciences Center, AMC Campus, 1600 Pierce, Denver, CO 80214 (USA). E-mail: Jaime.Modiano{at}UCHSC.edu