Targeted disruption of the S1P2 sphingosine 1-phosphate receptor gene leads to diffuse large B-cell lymphoma formation.
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.
Cattoretti
Giorgio
G
Institute for Cancer Genetics and the Department of Pathology, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York, USA.
Mandelbaum
Jonathan
J
Lee
Nancy
N
Chaves
Alicia H
AH
Mahler
Ashley M
AM
Chadburn
Amy
A
Dalla-Favera
Riccardo
R
Pasqualucci
Laura
L
MacLennan
A John
AJ
D000818:Animals; D016175:B-Lymphocyte Subsets / Q000276:immunology; D015152:Blotting, Northern; D015139:Blotting, Southern; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D016130:Immunophenotyping; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D049349:Receptors, Lysosphingolipid / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics*; D016176:T-Lymphocyte Subsets / Q000276:immunology
D049349:Receptors, Lysosphingolipid