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

• Published in: Cancer research (Chicago, Ill.) Ill.), 2009-11, Vol.69 (22), p.8686-8692
• Main Authors: CATTORETTI, Giorgio, MANDELBAUM, Jonathan, LEE, Nancy, CHAVES, Alicia H, MAHLER, Ashley M, CHADBURN, Amy, DALLA-FAVERA, Riccardo, PASQUALUCCI, Laura, MACLENNAN, A. John
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; B-Lymphocyte Subsets - immunology; Biological and medical sciences; Blotting, Northern; Blotting, Southern; Disease Models, Animal; DNA Mutational Analysis; Flow Cytometry; Fluorescent Antibody Technique; Genes, Tumor Suppressor - physiology; Hematologic and hematopoietic diseases; Humans; Immunohistochemistry; Immunophenotyping; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphoma, Large B-Cell, Diffuse - genetics; Lymphoma, Large B-Cell, Diffuse - immunology; Lymphoma, Large B-Cell, Diffuse - pathology; Medical sciences; Mice; Mice, Knockout; Mutation; Pharmacology. Drug treatments; Receptors, Lysosphingolipid - genetics; Signal Transduction - genetics; T-Lymphocyte Subsets - immunology; Tumors
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-09-1110

S1P(2) sphingosine 1-phosphate receptor signaling can regulate proliferation, survival, morphology, and migration in many cell types in vitro. Here, we report that S1P(2)(-/-) 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 S1P(2) loss may promote lymphomagenesis in part by disrupting GC B-cells homeostasis. With the sole exception of rare lung tumors, the effect of S1P(2) 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 S1P(2) 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 S1P(2) signaling may play a critical role in suppressing DLBCL formation in vivo. The high incidence of DLBCL in S1P(2)(-/-) 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.