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

¹ Institute for Cancer Genetics and the Department of Pathology, Herbert Irving Comprehensive Cancer Center, Columbia University and ² Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, New York, New York; ³ Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, Ohio, and ⁴ Department of Neuroscience, University of Florida College of Medicine, Gainesville, Florida

Requests for reprints: A. John MacLennan, Department of Molecular and Cellular Physiology, University of Cincinnati, 231 Albert Sabin Way, Cincinnati, OH 45267-0576. Phone: 513-558-0667; Fax: 513-558-5738; E-mail: john.maclen{at}uc.edu or L. Pasqualucci, Institute for Cancer Genetics, Columbia University, 1130 St. Nicholas Avenue, New York, NY 10032. Phone: 212-851-5248; Fax: 212-851-5256; E-mail: lp171{at}columbia.edu.

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]

Key Words: diffuse large cell lymphoma • G protein–coupled receptor • somatic hypermutation