Introduction of an activated RAS oncogene into murine bone marrow lymphoid progenitors via retroviral gene transfer results in thymic lymphomas.

Abstract

Activating mutations within the various RAS protooncogenes have been detected in many human and murine hematopoietic neoplasms. Their causal significance has been difficult to assess, partly due to the lack of an animal model directly linking these mutations to hematopoietic neoplasms. A high-titer, helper-free recombinant retrovirus was used to introduce an activated Harvey RAS gene under the transcriptional control of the Moloney leukemia virus LTR into murine bone marrow cells. Eleven of fifteen mice reconstituted with these bone marrow cells developed fatal thymic lymphomas 10-12 week post-transplant. Analysis of DNA and RNA from tumor cells revealed the integrated proviral genome and provirally encoded RAS mRNA respectively. Immunophenotyping and T-cell receptor rearrangement analysis of fresh tumor cells and of cell lines derived from these tumors showed them to be T-cells arrested midway through thymic development. Despite evidence of proviral integration in marrow cells of mice with thymic tumors, no other hematologic abnormalities were detected. The short latency and reproducibility of thymic lymphoma development in mice transplanted with marrow transduced with this retrovirus suggests a direct causal effect of expression of an activated RAS gene in the transformation of a bone-marrow-derived lymphoid progenitor.