The use of knockout mice reveals a synergistic role of the vav1 and rasgrf2 gene deficiencies in lymphomagenesis and metastasis

Abstract

Background: Vav1 and RasGRF2 are GDP/GTP exchange factors for Ras superfamily GTPases with roles in the development and/or effector functions of T-lymphocytes. Methodology/Principal Findings: Given that the phenotype of Vav1-/-, Rasgrf2-/- and Vav1-/-;Rasgrf2-/- mice has been studied so far in young animals, we decided to explore the long-term consequences of the inactivation of those loci in the immune system. Unexpectedly, our studies revealed that the inactivation of the Vav1 proto-oncogene favors the formation of lymphoblastic lymphoma-like tumors in aging mice. Those tumors, that can be found either localized exclusively inside the thymus or widely disseminated in hematopoietic and non-hematopoietic tissues, are composed of CD3+ lymphoblasts that display heterogeneous combinations of CD4 and CD8 surface markers. Interestingly, the additional deletion of the Rasgrf2 gene induces a shortening in the latency period for the development of those tumors, an increase in the percentage of disseminated tumors outside the thymus and, as a result, higher mortality rates. Conclusions/Significance: These data reveal unexpected negative roles for Vav1 and RasGRF2 in different stages of T-cell lymphoma progression. They also suggest that the inactivation of Vav1 function may represent an inadequate strategy to treat T-cell lymphomas, especially those associated with low levels of Rasgrf2 gene expression.