Bcl11b is a haploinsufficient tumor suppressor gene and expressed in many tissues such as thymus, brain and skin. Irradiated Bcl11b(+/-) heterozygous mice mostly develop thymic lymphomas, but the preference of Bcl11b inactivation for thymic lymphomas remains to be addressed. We produced Bcl11b(+/-) heterozygous and Bcl11b wild-type mice of p53(+/-) background and compared their incidence of gamma-ray induced thymic lymphomas. Majority of the tumors in p53(+/-) mice were skin tumors, and only 5 (36%) of the 1.4 tumors were thymic lymphomas. In contrast, Bcl11b(+/-) p53(+/-) doubly heterozygous mice developed thymic lymphomas at the frequency of 27 (79%) of the 34 tumors developed (P = 0.008). This indicates the preference of Bcl11b impairment for thymic lymphoma development. We also analyzed loss of the wild-type alleles in the 27 lymphomas, a predicted consequence given by gamma-irradiation. However, the loss frequency was low, only six (22%) for Bcl11b and five (19%) for p53. The frequencies did not differ from those of spontaneously developed thymic lymphomas in the doubly heterozygous mice, though the latency of lymphoma development markedly differed between them. This suggests that the main contribution Of irradiation at least in those mice is not for the tumor initiation by inducing allelic losses but probably for the promotion of thymic lymphoma development. (C) 2008 Elsevier Inc. All rights reserved.