Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas-University of Salamanca, Salamanca, Spain.
PLoS One. 2009 Dec 14;4(12):e8229. doi: 10.1371/journal.pone.0008229.
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.
Vav1 和 RasGRF2 是 Ras 家族 GTP 酶的 GDP/GTP 交换因子，在 T 淋巴细胞的发育和/或效应功能中起作用。
方法/主要发现：鉴于迄今为止已经在年轻动物中研究了 Vav1(-/-)、Rasgrf2(-/-)和 Vav1(-/-);Rasgrf2(-/-) 小鼠的表型，我们决定探索那些基因座在免疫系统中的长期失活后果。出乎意料的是，我们的研究表明，Vav1 原癌基因的失活有利于衰老小鼠中淋巴母细胞淋巴瘤样肿瘤的形成。这些肿瘤可以在胸腺内局部发现，也可以广泛分布在造血和非造血组织中，由显示 CD4 和 CD8 表面标志物异质性组合的 CD3(+)淋巴母细胞组成。有趣的是，Rasgrf2 基因的额外缺失会缩短这些肿瘤的潜伏期，增加胸腺外播散肿瘤的百分比，从而导致更高的死亡率。
结论/意义：这些数据揭示了 Vav1 和 RasGRF2 在 T 细胞淋巴瘤进展的不同阶段出人意料的负面作用。它们还表明，Vav1 功能的失活可能代表治疗 T 细胞淋巴瘤的一种不适当策略，尤其是那些与 Rasgrf2 基因表达水平低相关的肿瘤。
