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

S. P. Fosmire, R. Thomas, C. M. Jubala, J. W. Wojcieszyn, V. E.O. Valli, D. M. Getzy, T. L. Smith, L. A. Gardner, M. G. Ritt, J. S. Bell, K. P. Freeman, B. E. Greenfield, S. E. Lana, W. C. Kisseberth, S. C. Helfand, G. R. Cutter, M. Breen, Jaime F. Modiano

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)467-478
Number of pages12
JournalVeterinary pathology
Volume44
Issue number4
DOIs
StatePublished - Jul 2007

Bibliographical note

Funding Information:
We thank the owners and veterinarians who contributed cases, assisted with recruitment, and provided diligent follow-up. This work was supported in part by grants 1626, 2254, and 2214 from the AKC Canine Health Foundation (to JFM and MB), charitable donations from individuals, the Starlight Fund, the Kate Koogler Canine Cancer Research Fund, and the Monfort Family Foundation (to JFM) and by retention funds from the Integrated Department of Immunology and the University of Colorado Cancer Center (JFM).

Keywords

  • Canines
  • Cell cycle
  • Non-Hodgkin's lymphoma
  • Tumor suppressor genes

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