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Supplementary Figure 7 from Targeted Disruption of the S1P2 Sphingosine 1-Phosphate Receptor Gene Leads to Diffuse Large B-Cell Lymphoma Formation

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posted on 2023-03-30, 19:06 authored by Giorgio Cattoretti, Jonathan Mandelbaum, Nancy Lee, Alicia H. Chaves, Ashley M. Mahler, Amy Chadburn, Riccardo Dalla-Favera, Laura Pasqualucci, A. John MacLennan
Supplementary Figure 7 from Targeted Disruption of the S1P2 Sphingosine 1-Phosphate Receptor Gene Leads to Diffuse Large B-Cell Lymphoma Formation

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ARTICLE ABSTRACT

S1P2 sphingosine 1-phosphate receptor signaling can regulate proliferation, survival, morphology, and migration in many cell types in vitro. Here, we report that S1P2−/− mice develop clonal B-cell lymphomas with age, such that approximately half of the animals display this neoplasm by 1.5 to 2 years of age. Histologic, immunophenotypic, and molecular analyses revealed a uniform tumor phenotype with features of germinal center (GC)–derived diffuse large B-cell lymphoma (DLBCL). Tumor formation was preceded by increases in GC B cells and CD69+ T cells, as well as an increased formation of spontaneous GCs, suggesting that S1P2 loss may promote lymphomagenesis in part by disrupting GC B-cells homeostasis. With the sole exception of rare lung tumors, the effect of S1P2 gene disruption is remarkably restricted to DLBCL. In humans, 28 of 106 (26%) DLBCL samples were found to harbor multiple somatic mutations in the 5′ sequences of the S1P2 gene. Mutations displayed features resembling those generated by the IgV-associated somatic hypermutation mechanism, but were not detected at significant levels in normal GC B cells, indicating a tumor-associated aberrant function. Collectively, our data suggest that S1P2 signaling may play a critical role in suppressing DLBCL formation in vivo. The high incidence of DLBCL in S1P2−/− mice, its onset at old age, and the relative lack of other neoplasms identify these mice as a novel, and potentially valuable, model for this highly prevalent and aggressive human malignancy. [Cancer Res 2009;69(22):8686–92]

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