CYCLIN D1 BCL-1 COOPERATES WITH MYC GENES IN THE GENERATION OF B-CELL LYMPHOMA IN TRANSGENIC MICE

The chromosomal translocation t(11:14) is associated with human lymphoid neoplasia affecting centrocytic B-cells of intermediate differentiation; As a consequence the cyclin D1 (bcl-1) gene is juxtaposed to the immunoglobulin heavy chain enhancer E mu. To show that transcriptional activation of cyclin D1 is causally involved in the generation of B-cell neoplasia we have generated transgenic mice that Carry a cyclin D1 gene under the transcriptional control of the E mu element. E mu cyclin D1 transgenic mice show only very subtle alterations in the cycling behaviour of B cell populations in the bone marrow compared with normal mice add do not develop lymphoid tumours. However, E mu-directed coexpression of cyclin D1 and N-MYC or L-MYC in double transgenic mice reveals a strong cooperative effect between MYC and cyclin D1 provoking the rapid development of clonal pre-B and B-cell lymphomas. Interestingly, crossing of cyclin D1 transgenic mice with E mu L-myc transgenics that express their transgene in both B- and T-cells but predominantly develop T-cell tumours leads in double transgenics exclusively to B-cell neoplasia. The data presented here demonstrate that transcriptional activation of cyclin D1 can oncogenically transform B-cells in concert with a myc gene. They establish cyclin D1 as a protooncogene whose activity appears to depend on a specific cell type as well as on a specific cooperating partner and link disturbances in the regulation of cell cycle progression to the development of human malignancies.