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In this study, a mouse strain (TLL) that spontaneously develops T-cell lymphomas/leukemia with an early onset and high incidence was established and characterized. All tumors analyzed were found to express the alpha,beta T-cell receptor, and the majority of them had a mature, CD3+CD4+CD8- immunophenotype. In a few cases, tumors with a more immature CD3+CD4+CD8+ phenotype were isolated. Expanded phenotyping using a broad panel of lymphocyte differentiation markers confirmed the mature T-cell phenotype of the tumors. Histologic and cell cycle analysis of the tumors revealed an aggressive lymphoblastic malignancy with a very high proliferation rate and widespread engagement of bone marrow and lymphoid as well as nonlymphoid organs. Thus, the TLL mouse strain represents a unique model for the analysis of the oncogenesis and progression of mature T-cell tumors and for the development of therapeutic measures to combat such tumors.

Background: Moloney murine leukemia virus (Mo-MLV) has proven valuable for studies of the pathogenesis of malignant lymphoma. Inoculation of newborn mice induces T cell lymphoma with 100% incidence. The TLL (T cell lymphoma/leukemia)-strain was previously established and was shown to spontaneously develop T cell lymphoma at high frequency.

Materials and Methods: Differential screening of cDNA libraries was performed to discover an involvement of Mo-MLV and genomic sequencing was used to identify the chromosomal position of Mo-MLV proviral integration sites. Immunophenotypes of the tumors were established by flow cytometry. Disease frequency curves were created according to the Kaplan-Meier method.

Results: Two independent Mo-MLV germ line integrations were characterized on chromosomes 2 and 14, giving rise to two substrains of mice denoted TLL-2 and TLL-14. The chromosomal position of the integrated provirus affected the frequency of disease, as well as the immunophenotype of the tumors.

Conclusion: The data suggest that factors influencing the transcriptional activity of the chromosomal regions, leading to differences in proviral expression, could underlie the observed difference in tumor frequency.

Celecoxib, an inhibitor of cyclooxygenase-2, is a promising novel antitumor agent with pleitropic mechanisms of action. Whereas this drug induces growth arrest and apoptosis of B-lymphoma cells, its effect against aggressive T-cell neoplasms remains to be studied. We therefore evaluated Celecoxib therapy of immunocompetent mice transplanted with lymphoblastic T-cell lymphomas. Oral Celecoxib in clinically relevant and non-toxic doses did not affect the degree of hypersplenism or the number of viable lymphoma cells. The clinical deterioration of Celecoxib-treated mice was not different from untreated controls. The impact of adding Celecoxib (60 mg/kg) to cyclophosphamide (200 mg/kg x 1, i.p.) was assessed but showed no benefit compared to cyclophosphamide alone. Thus, Celecoxib lacks effect against lymphoblastic T-cell lymphoma in mice.