Multiple studies have begun to define a role for Vav in the development and progression of hematological malignancies. Transgenic mice have been generated with Vav1, 2, 3, and Rasgrf2 null alleles individually and in combination, and as mentioned above, these animals have defects in T-cell development and activation. Somewhat unexpectedly, longitudinal studies of Vav1 null mice revealed an increased incidence of aggressive lymphoblastic-like T-cell leukemia/lymphomas [32
]. The latency to the development of this murine T-cell leukemia/ lymphoma decreased and the incidence increased when Rasgrf2, a GEF with specificity for Ras and Rho/Rac GTPases, was additionally deleted from the genome in these mice. Examination of the immunophenotypic characteristics reveal the T-cell leukemia/lymphoma to be similar to those that develop spontaneously in older mice.
This increased development of T-cell lymphoblastic- like tumors in Vav1 null mice was unexpected given previous data implicating Vav1 as a proto-oncogene; indeed, this result complicates predictions of possible efficacy of Vav1-targeted small molecule inhibitors on the development and progression of human cancer. Given that Vav1 plays a role in the normal selection of mature thymocytes during development, one possibility is that Vav1 may help to reduce the negative selection of T-cell clones with potentially neoplastic rearrangements of somatic DNA during development. Alternatively, Dumont et al. [25
] have shown that deletion of both the Vav and Rac family in mice leads to upregulation of Notch signaling during early thymic development. The role of gain of function Notch1 alterations in the development of murine and human T-cell lymphoblastic lymphoma has been well established [33
], and thus it is tempting to speculate that Vav and Rac signalling alterations lead to T-cell lymphoblastic leukemia/ lymphoma through deregulation of Notch signaling ().
Figure 3 Proposed model of Vav1 deletion mediated murine T-cell lymphoblastic leukemia/lymphoma genesis. Deletion of both Vav and Rac family genes in mice leads to upregulation of Notch signaling during early thymic T-cell development and may contribute to the (more ...)
Interestingly, Berquam-Vrieze et al. describe their results with a novel forward genetic screen where they induce T-cell lymphoblastic leukemia/ lymphomas in mice by targeting mutational transposons to specific developmental stages of thymocytes [34
]. When they conditionally delete Vav from hematopoetic stem cells and examine the resultant T-cell leukemia for transposon mediated driver mutations, mutations in Notch1 were frequently found (72%), again emphasizing the connection between Vav signaling, Notch activation, and the development of T-cell malignancies. When the T-cell leukemia is induced in a later stage of T-cell development using an alternate transgene to Vav (Lck), the driver mutations are no longer found in Notch1.
The first human hematological malignancies that provided evidence of deregulated Vav1 was B-cell chronic lymphocytic leukemia (B-CLL). Prieto-Sanchez et al. [35
] examined Vav1 protein levels and phosphorylation status in 118 unselected cases of hematologic neoplasms which included myeloproliferative neoplasms and a variety of B-cell malignancies. They found that Vav1 was phosphorylated and overexpressed in 10 of 14 cases of B-CLL with 13q deletion. Vav1 protein levels were not altered in any of the myeloproliferative neoplasms examined.
An expression profiling study by Hollmann et al. [36
] revealed correlation between the expression of Vav1 and CD40-mediated apoptosis in diffuse large B-cell lymphoma cell lines. They found that Vav1 expression may have a role in the disparity between DLBCL cell lines sensitive to CD40 stimulation and those resistant to it. The cell lines resistant to CD40 induced apoptosis had reduced NF-κB activation and markedly reduced Vav1 levels. Interestingly, the authors found an association between increased Vav1 expression and a higher proliferative index, and the post-germinal center marker Irf-4. While it is unclear whether accentuation or reduction of Vav levels is the best approach to address the malignant B-cell phenotype, there is clear data in support of the role of Vav1 regulation in the survival of normal B-cells [23
]. In a malignant T-cell line, Yin, et. al. [37
] has demonstrated a correlation between increased Vav1 expression and increased Bcl2 expression which is associated with decreased sensitivity to fas-mediated apoptosis, but to our knowledge, this has not been described in malignant B-cells.
In acute myeloid leukemia (AML), several studies have shown that Vav1 is required for ATRA induced differentiation of human promyelocytic leukemia cell lines to neutrophils as well as PMA induced maturation of these same cell lines to monocytes/macrophages [38
]. Interestingly, evidence is presented that Vav1 is directly recruited to the promoter of CD11b, an integrin selectively expressed on the surface of mature granulocytes, and may participate in transcriptional regulation of CD11b during ATRA induced differentiation [41
]. However, there is no evidence that Vav1 has a tumor suppressor role in AML as repressed Vav1 expression has not been associated with AML in humans nor has it lead to the development AML in Vav-deficient mice.