We use AKR/J-streaker mice homozygous for the autosomal recessive mutation nu?str? (nude streaker) to assess the role of thymic epithelium (T.E.) in leukemogenesis. Unlike AKR/J mice, the nu?str?/nu?str? mice are congenitally athymic, lack hair, do not develop recombinant retroviruses and have a low incidence of spontaneous leukemia. Like AKR/J mice, they are infected from birth with ecotropic and xenotropic murine leukemia viruses (MuLV). The hypothesis states that radioresistant AKR/J T.E. is required for transformation of nu?str?/nu?str? bone marrow cells into preleukemic cells and conversion of these preleukemic cells into leukemic cells during thymic differentiation.
The aims are to determine if T.E. grafts are necessary for: (1) generation of recombinant MuLV in nu?str?/nu?str? mice; (2) leukemic transformation of nu?str?/nu?str? lymphoid cells; and (3) leukemia development after injection of cloned recombinant AKR MuLV into thymus donors for nu?str?/nu?str? mice.
A fourth aim i s to determine if preleukemic cells are present in the bone marrow of nu?str?/nu?str? mice.
Aims 1 and 2 will be met by grafting irradiated thymuses from leukemia-resistant and leukemia-susceptible strains into nu?str?/nu?str? mice followed by observation for development of recombinant MuLV and leukemia.
Aim 3 will involve injection of cloned, recombinant AKR/J MuLV into neonatal thymuses prior to grafting of nu?str?/nu?str? by observation for leukemia development.
Aim 4 will involve transplantation of nu?str?/nu?str? bone marrow into sublethally irradiated (AKR X DBA/2)F?1? recipients with observation for leukemia incidence. Phenotype analysis of all leukemias that develop in these experiments will be performed by flow cytometry to assess donor versus recipient origin of the leukemic cells, as well as their T, B, or null cell lineage. These studies will improve our knowledge of the role of the thymus in murine T-cell leukemogenesis. There is preliminary evidence that both irradiated and unirradiated neonatal thymus grafts from both leukemia-resistant and leukemia-susceptible strains smplify expression of MuLV in AKR-streaker mice approximately 3-8 months after transplantation. Grafts of irradiated thymuses from both leukemia-susceptible and leukemia-resistant strains effectively reconstitute T-cell immunity in the AKR-streaker recipients as measured by mitogen, mixed lymphocyte culture, and cell-mediated lympholysis. (IP)
| Tempelis, L D (1987) Thymic epithelium controls thymocyte expression of preleukemic phenotype and leukemogenic retroviruses. J Immunol 138:3555-65 |
