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2006 ACVP Annual Meeting

2006 Christopher T. Starost Memorial Oncology Scholarship Recipient Abstracts

First Place

DEVELOPMENT OF A XENOGRAFT MOUSE MODEL OF HUMAN T-CELL LYMPHOTROPHIC VIRUS TYPE 1 ASSOCIATED ADULT T CELL LEUKEMIA/LYMPHOMA FOR USE IN PRECLINICAL EFFICACY AND THERAPEUTIC STUDIES.B. Zimmerman, C. Parrula, S. Niewiesk, and M.D. Lairmore, Department of Veterinary Biosciences, The Ohio State University, Columbus, OH.

Human T-lymphotrophic virus type 1 (HTLV-1), a member of the deltaretrovirus family, is the causative agent of adult T cell leukemia/ lymphoma (ATL). ATL is a highly aggressive T cell malignancy with a leukemic phase characterized by circulating activated CD4+/CD25+ T cells. ATL patients have a poor prognosis due to the resistance of ATL to conventional chemotherapies. Consistent cellular alterations within these cells, such as NF-kB activation, make targeted therapeutics a more likely alternative therapy to conventional chemotherapeutics. We developed a NOD/SCID ATL mouse model in which we tested therapies that target NF-B or HSP-90. ATL derived, C8166-45 cells (1x 107), were injected intraperitoneally into female NOD/SCID mice. Tumor burden was quantified by measuring -2 microglobulin by ELISA. Neoplastic infiltrates were evaluated histopathologically. Infiltrates were present in the peritoneum, pancreas, and uterus of all control animals. Other organs were variably infiltrated with neoplastic cells. Control mice succumb to multicentric lymphoma within 3-4 weeks. A dual armed trial was designed to test anti-tumor efficacy of PS-341, a 26 S proteasome inhibitor that prevents the breakdown of the inhibitor of NF-kB and the HSP-90 inhibitor 17-AAG, which promotes the accumulation of ubiquitinated proteins within the cell. Our data indicates that the combination of PS-341 and 17-AAG promotes apoptosis of the ATL cell line, both in vitro and in the xenograft NOD/SCID mouse model. This dual targeted therapy offers promise to decrease tumor burden and increase mean survival time of ATL patients.

Second Place

NFkappaB AND BCL3 COOPERATIVELY TRANSACTIVATE THE PARATHYROID HORMONE-RELATED PROTEIN PROMOTER IN ADULT T-CELL LEUKEMIA/LYMPHOMA. M.V.P. Nadella1, W.P. Dirksen1, K.S. Nadella2, S. Shu1, V. Richard3, T.J. Rosol1,4.1Department of Veterinary Biosciences, 2Human Cancer Genetics, 4Center for Retrovirus Research, The Ohio State University, Columbus, OH; 3 Pfizer, Sandwich Laboratories, Kent, UK.

Parathyroid hormone-related protein (PTHrP) plays a primary role in the development of humoral hypercalcemia of malignancy (HHM) that occurs in the majority of patients with adult T-cell leukemia/lymphoma (ATLL) and T-lymphotropic virus type-1 (HTLV-1) infection. Previously, we established a SCID/bg mouse model of ATLL with RV-ATL cells and showed that these cells constitutively express high levels of PTHrP utilizing the P2 and P3 promoters resulting in HHM. HTLV-1-Tax activates and induces nuclear translocation of transcription factor NFB, which plays a crucial role in transformation of T cells by HTLV-I. However, Tax is not expressed significantly in leukemic cells from ATLL patients. In this study, we report the characterization of a novel NFB binding site in the P2 promoter of PTHrP that is homologous to the consensus NFB binding sequence. The binding proteins to the consensus NFB sequence in Tax-expressing cells consisted mostly of p50/c-Rel heterodimers and in ATL cells, which do not express Tax, had predominantly p50/p50 homodimers and some p50/p65 heterodimers. Using electrophoretic mobility shift assays (EMSA) we found that a single complex formed on the PTHrP P2 promoter in Tax-expressing T-cells, but two complexes in ATLL cells. The complexes in Tax-expressing cells were composed of p50 and c-Rel, but the complexes in the RV-ATL cells contained p50 and other yet unidentified protein(s). BCL3 transactivates genes in conjunction with the NFB p50 and p52 homodimers. We report the expression of BCL3 in the nuclear and cytoplasmic fractions of HTLV-1-positive cells and ATLL cells. Transient cotransfection of NIH3T3 cells with NFB expression plasmids and a PTHrP P2 luciferase reporter-plasmid has shown that NFB p50 and BCL3 cooperatively upregulated the PTHrP P2 promoter. Our data demonstrated that transcriptional regulation of PTHrP in ATLL cells can be controlled, in part, by NFB activation and also suggests a Tax-independent mechanism of activation of PTHrP in ATLL due to differential NFB subunit activation.

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