BcII Ib mutations identified in murine lymphomas increase the proliferation rate of hematopoietic progenitor cells

Background: The telomeric region of mouse chromosome 12 has previously shown frequent allelic loss in murine lymphoma. The BcII Ib gene has been identified and suggested as a candidate tumor suppressor gene within this region. In this study, we aimed to elucidate whether BcII Ib is mutated in lymphomas with allelic loss, and whether the mutations we detected conferred any effect on cell proliferation and apoptosis. Methods: Mouse lymphomas induced by 1,3-butadiene or 2',3'-dideoxycytidine were analysed for mutations in the BcII Ib gene using single strand conformation analysis and direct DNA sequencing. Effects on cell proliferation by the detected mutations were studied by expressing wild-type and mutant BcII Ib in the cytokine-dependent hematopoietic progenitor cell line FDC-PI, lacking endogenous BcII Ib expression. Results: Missense and frameshift (FS) mutations were identified in 7 of 47 tumors (15%). Interestingly, all mutations were found between aminoacids778-844 which encode the three C-terminal DNA-binding zinc fingers. In FDC-P1 cells, wild-type BcII Ib suppressed cell proliferation, whereas the mutated versions (S778N, K828T, Y844C and FS823) enhanced proliferation several-fold. Conclusion: The genetic alterations detected in this study suggest that the three C-terminal zinc fingers of BcII Ib are important for the DNA-binding. Cell proliferation was suppressed by overexpression of wild-type BcII Ib but enhanced by mutant BcII Ib, indicating that these mutations may be an important contributing factor to lymphomagenesis in a subset of tumors.