Inactivation of the p16 cyclin-dependent kinase inhibitor in high-grade canine non-Hodgkin's T-cell lymphoma.

TitleInactivation of the p16 cyclin-dependent kinase inhibitor in high-grade canine non-Hodgkin's T-cell lymphoma.
Publication TypeJournal Article
Year of Publication2007
AuthorsFosmire SP, Thomas R, Jubala CM, Wojcieszyn JW, Valli VEO, Getzy DM, Smith TL, Gardner LA, Ritt MG, Bell JS, Freeman KP, Greenfield BE, Lana SE, Kisseberth WC, Helfand SC, Cutter GR, Breen M, Modiano JF
JournalVeterinary pathology
Date Published2007 Jul
KeywordsAnimals, Cyclin-Dependent Kinase Inhibitor p16, Dog Diseases, Dogs, Female, Gene Expression Regulation, Neoplastic, Gene Silencing, Lymphoma, B-Cell, Lymphoma, T-Cell, Male, Retinoblastoma Protein

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.

Alternate JournalVet. Pathol.