Induction of B-cell lymphoma by UVB radiation in p53 haploinsufficient mice.
BACKGROUND
The incidence of non-Hodgkin's lymphoma has increased over recent years. The exact etiology of lymphoma remains unknown. Ultraviolet light exposure has been associated with the development of internal lymphoid malignancies and some reports suggest that it may play a role in the development of lymphoma in humans. Here we describe the characterization and progression of lymphoma in p53 heterozygous mice exposed to UVB irradiation.


METHODS
UVB-irradiated p53+/- mice developed enlargement of the spleen. Isolated spleen cells were transplanted into Rag deficient hosts. The UV-induced tumor cells were analyzed by flow cytometry. The tumor cells were tagged with GFP to study their metastatic potential. SKY and karyotypic analysis were carried out for the detection of chromosomal abnormalities. Functional assays included in vitro class switch recombination assay, immunoglobulin rearrangement assay, as well as cytokine profiling.


RESULTS
UVB-exposed mice showed enlargement of the spleen and lymph nodes. Cells transplanted into Rag deficient mice developed aggressive tumors that infiltrated the lymph nodes, the spleen and the bone marrow. The tumor cells did not grow in immune competent syngeneic C57Bl/6 mice yet showed a modest growth in UV-irradiated B6 mice. Phenotypic analysis of these tumor cells revealed these cells are positive for B cell markers CD19+, CD5+, B220+, IgM+ and negative for T cell, NK or dendritic cell markers. The UV-induced tumor cells underwent robust in vitro immunoglobulin class switch recombination in response to lipopolysaccharide. Cytogenetic analysis revealed a t(14;19) translocation and trisomy of chromosome 6. These tumor cells secret IL-10, which can promote tumor growth and cause systemic immunosuppression.


CONCLUSIONS
UV-irradiated p53+/- mice developed lymphoid tumors that corresponded to a mature B cell lymphoma. Our results suggest that an indirect mechanism is involved in the development of internal tumors after chronic exposure to UV light. The induction of B cell lymphoma in UV-irradiated p53 heterozygous mice may provide a useful model for lymphoma development in humans.
Department of Immunology and the Center for Cancer Immunology Research, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Nahum
N
Puebla-Osorio
Yasuko
Y
Miyahara
Sreevidya
S
Coimbatore
Alberto Y
AY
Limón-Flores
Nasser
N
Kazimi
Stephen E
SE
Ullrich
Chengming
C
Zhu
D000818:Animals; D002869:Chromosome Aberrations; D016207:Cytokines / Q000096:biosynthesis; D016158:Genes, p53; D057895:Haploinsufficiency; D016753:Interleukin-10 / Q000096:biosynthesis / Q000378:metabolism; D016393:Lymphoma, B-Cell / Q000209:etiology* / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D014466:Ultraviolet Rays
D016207:Cytokines; D016753:Interleukin-10
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