Bcl11b Heterozygous Mice are Susceptible to N-methyl-N-nitrosourea-induced Thymic Lymphomas

N-methyl-N-nitrosourea (MNU) is an alkylating agent that can modify the guanine base in DNA.The mode of mutation induction differs from that of radiation, which generates large mutations such as chromosomal deletion and translocation. Our previous studies showed that Bcl11b is a tumor suppressor gene and that Bcl11b+/- heterozygous mice are susceptible to γ-ray induced thymic lymphomas. This study investigates whether or not the Bcl11b+/- genotype also provides susceptibility to MNU-induced thymic lymphomas. The results showed that loss of one copy of the Bcl11b gene contributed to lymphomagenesis, indicating that Bcl11b can suppress MNUinduction of thymic lymphomas. Interestingly, loss of the wild-type Bcl11b allele was not detected in those lymphomas, contrasting with the finding ofa high frequency of the loss in the γ-ray induced Bcl11b+/- thymic lymphomas. On the other hand, epigenetic inactivation of Bcl11b was observed in 74% (14/19) of the Bcl11b+/- lymphomas. This may be the main contributor to the loss of Bcl11b function and probably affects the elevation of lymphoma incidence and the shortening of the latency in Bcl11b+/- mice when MNU is administrated