The stromal gene encoding the CD274 antigen as a genetic modifier controlling survival of mice with γ-radiation-induced T-cell lymphoblastic lymphomas.
Using an inter-specific subcongenic strain, Nested Recombinant Haplotype 3 (NRH3), generated between two mouse strains showing extreme differences in γ-radiation-induced thymic lymphoma susceptibility (SEG/Pas and C57BL/6J), we have identified a critical region on chromosome 19 that regulates survival of mice suffering from T-cell lymphoblastic lymphomas. Mapped on this region, the gene encoding the Cd274 ligand is able to trigger an inhibitory effect that modulates T-cell receptor (TCR) signalling and affects thymocyte maturation. Interestingly, this gene shows differential expression between thymic stromal cells from both strains in early response to a single sublethal γ-ray dose, but is inhibited in T-cell lymphoblastic lymphomas. Furthermore, we have identified several polymorphisms in the complementary DNA sequence of this gene that affect the affinity for its Cd279 receptor and are able to induce a differential rate of thymocyte apoptosis. Taken together, our data are consistent with Cd274 acting as a genetic modifier that influences the survival of γ-radiation-induced T-cell lymphoma-bearing mice. The data similarly support the idea of a co-evolution of tumour cells and associated stromal cells to generate a favourable microenvironment for T-cell lymphoma growth.
Santos
J
J
Departamento de Biología Celular e Inmunología, Centro de Biología Molecular Severo Ochoa (CBMSO), Consejo Superior de Investigaciones Científicas-Universidad Autínoma de Madrid, Madrid, Spain.
González-Sánchez
L
L
Villa-Morales
M
M
Ors
I
I
López-Nieva
P
P
Vaquero
C
C
González-Gugel
E
E
Fernández-Navarro
P
P
Roncero
A M
AM
Guenet
J-L
JL
Montagutelli
X
X
Fernández-Piqueras
J
J
D000818:Animals; D017209:Apoptosis; D018122:B7-1 Antigen / Q000235:genetics*; D060890:B7-H1 Antigen; D006239:Haplotypes; D016399:Lymphoma, T-Cell / Q000235:genetics* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D009381:Neoplasms, Radiation-Induced / Q000235:genetics* / Q000473:pathology; D010455:Peptides / Q000235:genetics*; D011110:Polymorphism, Genetic; D016019:Survival Analysis
D018122:B7-1 Antigen; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D008562:Membrane Glycoproteins; D010455:Peptides