The Use of Knockout Mice Reveals a Synergistic Role of the Vav1 and Rasgrf2 Gene Deficiencies in Lymphomagenesis and Metastasis

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.