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.


RESULTS
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
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.
Ruiz
Sergio
S
Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas-University of Salamanca, Salamanca, Spain.
Santos
Eugenio
E
Bustelo
Xosé R
XR
D000818:Animals; D015536:Down-Regulation / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007938:Leukemia / Q000235:genetics / Q000473:pathology; D008223:Lymphoma / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D009362:Neoplasm Metastasis / Q000235:genetics / Q000473:pathology; D000090063:Proto-Oncogene Mas; D051567:Proto-Oncogene Proteins c-vav / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013953:Thymus Neoplasms / Q000473:pathology; D020663:ras Guanine Nucleotide Exchange Factors / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism
C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D051567:Proto-Oncogene Proteins c-vav; C504490:RASGRF2 protein, human; D012333:RNA, Messenger; C504491:Rasgrf2 protein, mouse; C496618:VAV1 protein, human; C496619:Vav1 protein, mouse; D020663:ras Guanine Nucleotide Exchange Factors