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

Abstract

BackgroundVav1 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 FindingsGiven 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/SignificanceThese 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.

The protooncogene Vav1 regulates murine leukemia virus-induced T-cell leukemogenesis

“…Compare with our results (Fig. 2), aging leukemic Vav1 −/− mice do not show massive thymic enlargement 16 . It could be that initial leukemic cells are produced in a more mature phenotype in aging mice, which do not localize in the thymus.…”

βArrestin1 Regulates the Guanine Nucleotide Exchange Factor RasGRF2 Expression and the Small GTPase Rac-mediated Formation of Membrane Protrusion and Cell Motility

“…Similarly, reduced rasgrf2 gene or protein expression was observed in mammary carcinoma tissues (30), in non-small cell lung cancers (31), and in benign colorectal adenoma as well as invasive colon carcinomas (32). Restoration of RasGRF2 expression resulted in a 56% reduction of colony formation of the colorectal cancer cell line HCT-116 (32), and deletion of RasGRF2 accelerated development of lymphoblastic lymphoma-like tumors in mice (33), suggesting a tumor-suppressive role for RasGRF2. A recent study showed that ␤Arr1 functions as an E3 ligase adaptor in the nucleus to mediate p53 degradation and accumulation of DNA damage in response to chronic stress (23).…”

Activating mutations and translocations in the guanine exchange factor VAV1 in peripheral T-cell lymphomas

“…Moreover, the identification here of additional VAV1 genetic alterations in PTCL, including a novel recurrent in-frame deletion resulting in the loss of amino acids 778-786 in the linker region between the SH2 and C-terminal SH3 domains of VAV1, further supports a pathogenic role for VAV1 signaling in T-cell transformation. However, constitutive genetic loss of Vav1 is associated with the development of aggressive T-cell lymphoblastic lymphomas in aged mice (35,36), probably as a result of deregulated oncogenic pathways activated in response to defective Vav1 signaling (37).…”