Bcl11b heterozygosity promotes clonal expansion and differentiation arrest of thymocytes in γ‐irradiated mice

Bcl11b encodes a zinc‐finger transcription factor and functions as a haploinsufficient tumor suppressor gene. Bcl11b KO/KO mice exhibit differentiation arrest of thymocytes during β‐selection as has been observed with other mouse models involving knockouts of genes in the Wnt/β‐catenin signaling pathway. Recurrent chromosomal rearrangement at the BCL11B locus occurs in human T‐cell leukemias, but it is not clear how such rearrangement would contribute to lymphomagenesis. To address this issue, we studied clonal cell growth, cell number, and differentiation of thymocytes in Bcl11b KO/+ mice at different time points following γ‐irradiation. Analysis of D‐J rearrangement at the T cell receptor β‐chain ( TCRβ ) locus and cell surface markers by flow cytometry revealed two distinct populations of clonally growing thymocytes. In one population, thymocytes share a common D‐J rearrangement but retain the capacity to differentiate. In contrast, thymocytes in the second population have lost their ability to differentiate. Since the capacity to self renew and differentiate into multiple cell lineages are fundamental properties of adult stem cells, the differentiation competent population of thymocytes that we have isolated could potentially function as cancer stem cells. We also demonstrate increased expression of β‐catenin, a well‐known oncogenic protein, in Bcl11b KO/+ thymocytes. Collectively, the Bcl11b KO/+ genotype contributes to clonal expansion and differentiation arrest in part through an increase in the level of β‐catenin. ( Cancer Sci 2010)