Bcl11b heterozygous genotype promotes development of thymic prelymphoma cells in γ-irradiated mice

Abstract

Premalignant lesions are strongly associated with the development of malignant neoplasia and must exist in γ-ray induced mouse atrophic thymus that persists until lymphoma development. Our previous studies of atrophic thymuses showed the presence of two different types of clonally expanding thymocytes. One is C type thymus that shows limited D-J rearrangement patterns at the TCRβ locus, indicative of clonal expansion in approximately 40% of thymuses at 40 days after. Those C type thymocytes mainly consist of CD4+CD8+ double positive (DP) cells, aberrant DP thymocytes bearing a given type of TCRβ chain on cell surface. The other is T type thymus that does not show limited D-J rearrangement patterns but shows allelic loss at Bcl11b. This suggested that loss of a Bcl11b allele probably contributed to clonal expansion and lymphoma development. Here we study the effect of Bcl11b heterozygous genotype on the development of C type thymocytes in Bcl11b ^KO/+ mice. Most of thymuses at 30 days after 3Gy of γ-ray at the age of 10 weeks showed decrease in cell number and approximately 50% of these thymuses consisted of C type thymocytes. Those thymuses were classified into three groups: (1) normal or T type thymus, (2) C type thymus consisting of CD4+CD8+DP cells, and (3) C type thymus consisting of immature cells before differentiating into DP cells, which was not found in irradiated wild type mice. These results suggest that Bcl11b heterozygous genotype promotes the development of C type thymocytes and differentiation arrest of C type thymocytes. In contrast, thymuses in mice irradiated at the age of 4 weeks rarely exhibited those changes, suggesting marked age-dependency in Bcl11b ^KO/+ mice.