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Establishment and characterization of a mouse strain (TLL) that spontaneously develops T-cell lymphomas/leukemia
Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
Umeå University, Faculty of Medicine, Department of Medical Biosciences.
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1999 (English)In: Experimental Hematology, ISSN 0301-472X, E-ISSN 1873-2399, Vol. 27, no 4, 682-688 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
1999. Vol. 27, no 4, 682-688 p.
Keyword [en]
T-cell lymphoma, t-cell leukemia, cd3 antigen, cd4 antigen, cd8 antigen
National Category
Cancer and Oncology
Research subject
Oncology
Identifiers
URN: urn:nbn:se:umu:diva-35017DOI: 10.1016/S0301-472X(99)00003-XPubMedID: 10210326OAI: oai:DiVA.org:umu-35017DiVA: diva2:328261
Available from: 2010-07-02 Created: 2010-07-02 Last updated: 2017-12-12Bibliographically approved
In thesis
1. Establishment and characterization of a murine T-cell lymphoma/leukemia model
Open this publication in new window or tab >>Establishment and characterization of a murine T-cell lymphoma/leukemia model
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Mouse models of human disease are valuable tools for studying pathogenesis and for evaluating novel therapies. T-cell lymphoma is a relatively rare disease in humans, affecting 100-150 persons yearly in Sweden. It exists in both aggressive and more indolent forms. We have established a mouse model for an aggressive T-cell lymphoma, the T-cell lymphoma/leukemia (TLL) mouse. In the present thesis, the TLL mouse model was characterized and used for experimental therapeutic and primary prevention studies.

The TLL mouse was established unintentionally in our laboratory during work on VH-gene replacement in a “knock-in” mouse experimental setting. The generated chimeras all developed aggressive T-cell lymphomas affecting the lymphoid organs, lungs, kidneys and liver. The lymphoma phenotype segregated from the targeted locus and we could demonstrate the presence of Moloney murine leukemia virus (MMLV) in the germline of the affected mice. MMLV is a retrovirus known to induce T-cell lymphomas when inoculated in newborn mice.  We further characterized two TLL substrains; TLL-2 and TLL-14 carrying the proviral integrations on chromosomes 2 and 14 respectively. Significant differences were found between the substrains regarding lymphoma frequency and immunophenotype, the TLL-14 substrain developing tumors with higher frequency than TLL-2 and with a more mature immunophenotype.

A transfer model was developed in which TLL cells could be readily transferred intravenously to syngenic recipients causing aggressive lymphomas. The transfer model was used in a therapeutic study where the selective COX-2 inhibitor celecoxib was evaluated as a single agent and in combination with the established anti-tumor agent cyclophosphamide. The study was based on results from other tumor types that have indicated celecoxib, originally an anti-inflammatory and analgetic drug, to have possible anti-tumor effects. In our TLL model, however, we could not demonstrate any benefit of celecoxib monotherapy or any additive effect to cyclophosphamide.

Dietary fatty acids, in particular omega-3 fatty acids, have been a focus of public and scientific interest due to observed effects on the prevention of cardiovascular disease, cancer and inflammatory conditions. In addition, omega-3 fatty acids inhibit T-cell proliferation in vitro. We supplemented the diet of TLL mice with omega-3 and omega-6 fatty acids respectively and could demonstrate a significant delay in lymphoma onset between 5-8 months of age in the group receiving an omega-3 rich diet.

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2010. 66 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1348
Keyword
Mouse model, T-cell lymphoma, Moloney murine leukemia virus, proviral integration, lymphomagenesis, COX-2, omega 3
National Category
Cancer and Oncology
Research subject
Oncology
Identifiers
urn:nbn:se:umu:diva-35195 (URN)978-91-7264-992-7 (ISBN)
Public defence
2010-10-01, Sal B, 9tr, by 1D, Norrlands universitetssjukhus, Umeå, 09:00 (English)
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Available from: 2010-09-08 Created: 2010-08-09 Last updated: 2010-09-08Bibliographically approved

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