TLI1, A RESISTANCE LOCUS FOR CARCINOGEN-INDUCED T-LYMPHOMA

Within 180 days after injection with N-methyl-N-nitrosourea (MNU), 83.5% of AKR/J mice and 37.5% of BALB/cJ mice developed T-lymphoma. The high tumor incidence was a dominant trait, as 93% of MNU-injected F1 mice developed T-lymphoma. A genome screen of 285 MNU-injected F2 mice identified a locus, designated T-lymphoma Induced 1 or Tli1, in a ∼10-cM interval on central Chr 1 between D1Mit87 and D1Mit423 with significant linkage to the incidence of MNU-induced T-lymphoma (P= 0.0004). Injection of BALB/cJ.AKR/J–Tli1 congenic mice with MNU confirmed the presence of Tli1 on central Chr 1. Mice homozygous for the BALB/cJ allele (Tli1 bb) were over-represented in the tumor-free F2 mice, while the inheritance of parental alleles of Tli1 in tumor-bearing mice was close to expected. This suggests that the Tli1 b allele is recessive and suppresses MNU-induced T-lymphoma development in BALB/cJ mice and in Tli1 bb F2 mice. Furthermore, the kinetics of lymphoma development in BALB/cJ and the Tli1 congenic mice suggests that Tli1 b acts to suppress lymphomas developing late after injection with MNU. Two known genes that map in the identified genomic interval on central Chr 1 are candidates for Tli1:IL10, encoding the lymphokine IL10, and Cmkar4, encoding the chemokine receptor CXCR4.