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. 2012 Aug 1;1(5):600-608.
doi: 10.4161/onci.20225.

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

Sandra Kaminski  1 , Oumeya Adjali, Chantal Jacquet, Johan Garaude, Anne Keriel, Adeline Lassaux, Robert Hipskind, Marc Sitbon, Naomi Taylor, Martin Villalba
Affiliations

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

Sandra Kaminski et al. Oncoimmunology. .

Abstract

Vav1 is expressed exclusively in hematopoietic cells and is required for T cell development and activation. Vav1-deficient mice show thymic hypocellularity due to a partial block during thymocyte development at the DN3 stage and between the double positive (DP) and single positive (SP) transition. Vav1 has been shown to play a significant role in several non-hematopoietic tumors but its role in leukemogenesis is unknown. To address this question, we investigated the role of Vav1 in retrovirus-induced T cell leukemogenesis. Infection of Vav1-deficient mice with the Moloney strain of murine leukemia virus (M-MuLV) significantly affected tumor phenotype without modulating tumor incidence or latency. M-MuLV-infected Vav1-deficient mice showed reduced splenomegaly, higher hematocrit levels and hypertrophic thymi. Notably, Vav1-deficient mice with M-MuLV leukemias presented with markedly lower TCRβ/CD3 levels, indicating that transformation occurred at an earlier stage of T cell development than in WT mice. Thus, impaired T cell development modulates the outcome of retrovirus-induced T cell leukemias, demonstrating a link between T cell development and T cell leukemogenesis.

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Figures

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Figure 1. Survival and tumor incidence in mice after M-MuLV infection. Vav1+/+ (n = 44), Vav1+/− (n = 72) and Vav1−/− (n = 48) mice were infected with M-MuLV. The graph shows the cumulative incidence of leukemia based on enlarged lymphoid organs and hematocrit levels.
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Figure 2. Phenotype of M-MuLV-infected mice. Mice described in Figure 1 were analyzed for tumor phenotype. A) Hematocrits in the different mice populations were monitored one day before euthanasia. B) Spleen and thymus cellularity in M-MuLV-infected mice. C) Spleen weights in different mice populations. D) Size of thymi in different mice populations. Data were evaluated using Student’s t-test: * p < 0.05; **p < 0.01; ***p < 0.001.
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Figure 3. Thymocyte populations in M-MuLV infected mice. A) Flow cytometry analysis of thymi from control and M-MuLV infected mice. Cells were stained with anti-CD4 and anti-CD8 antibodies to distinguish CD4-/CD8- (DN), CD4+/CD8+ (DP), CD4+/CD8- (CD4+) and CD4-/CD8+ (CD8+) populations. B) Percentages of DN, DP, CD4+ and CD8+ from representative populations of mice (Vav1+/+ control (n = 6); Vav1−/− control (n = 6); Vav1+/+ M-MuLV (n = 4); Vav1−/− M-MuLV (n = 9)). The numbers in brackets reflect the mice whose plots are depicted in panel A. C) Representative histograms showing TCRβ expression in the CD4+/CD8- subset of different mice populations. Data were evaluated using Student’s t-test: * p < 0.05; **p < 0.01; ***p < 0.001.
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Figure 4. Impaired thymocyte development in Vav1−/− M-MuLV mice. A) Flow cytometric analysis of thymi from control and M-MuLV infected mice. Cells were stained with CD44 and CD25 antibodies to distinguish DN1 (CD44+/CD25-), DN2 (CD44+/CD25+), DN3 (CD44-/CD25+) and DN4 (CD44-/CD25-) subsets within the CD4-CD8- population. B) Percentages of DN1, DN2, DN3 and DN4 from representative populations of mice (Vav1+/+ control (n = 6); Vav1−/− control (n = 6); Vav1+/+ M-MuLV (n = 4); Vav1−/− M-MuLV (n = 9)). The numbers in brackets reflect the mice whose plots are depicted in panel A. Data were evaluated using Student’s t-test: * p < 0.05; **p < 0.01; ***p < 0.001.
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Figure 5. Cell cycle entry of different thymocyte populations. Thymocytes were stained with the corresponding antibodies to identify CD4-/CD8- (DN), CD4+/CD8+ (DP), CD4+/CD8- (SP4) and CD4-/CD8+ (SP8) cells and with an anti-Ki67 antibody to analyze cell cycle entry. A) The total percentages of cells and the percentages of Ki67+ cells in the different populations are shown in 3-d old (white bars) and adult (black bars) mice of both genotypes . B) Comparative analysis of Ki67 expression in the different populations between Vav1−/− and wild-type mice. Data represent the mean percentages ± SEM of three independent experiments with n = 3 mice per group. Data were evaluated using Student’s t-test: * p < 0.05; **p < 0.01; ***p < 0.001.
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Figure 6. Analysis of splenocyte populations in M-MuLV infected mice. (A) Expression of CD3, CD19, CD4 and CD8 in splenocytes (Vav1+/+ control (n = 8); Vav1−/− control (n = 8); Vav1+/+ M-MuLV (n = 36); Vav1−/− M-MuLV (n = 46)) were assessed by flow cytometry and bar graphs presenting the mean percentages ± SEM of splenocytes expressing CD3 and CD19 are shown. B) Graphs presenting the mean percentages ± SEM of splenocytes expressing CD4 and CD8 in the absence or presence of surface CD3 are shown. Data were evaluated using Student’s t-test: * p < 0.05; **p < 0.01; ***p < 0.001.
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