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

The chromosomal translocation t(11:14) is associated with human lympho id neoplasia affecting centrocytic B-cells of intermediate differentia tion; As a consequence the cyclin D1 (bcl-1) gene is juxtaposed to the immunoglobulin heavy chain enhancer E mu. To show that transcriptiona l activation of cyclin D1 is causally involved in the generation of B- cell neoplasia we have generated transgenic mice that Carry a cyclin D 1 gene under the transcriptional control of the E mu element. E mu cyc lin D1 transgenic mice show only very subtle alterations in the cyclin g behaviour of B cell populations in the bone marrow compared with nor mal mice add do not develop lymphoid tumours. However, E mu-directed c oexpression of cyclin D1 and N-MYC or L-MYC in double transgenic mice reveals a strong cooperative effect between MYC and cyclin D1 provokin g the rapid development of clonal pre-B and B-cell lymphomas. Interest ingly, crossing of cyclin D1 transgenic mice with E mu L-myc transgeni cs that express their transgene in both B- and T-cells but predominant ly develop T-cell tumours leads in double transgenics exclusively to B -cell neoplasia. The data presented here demonstrate that transcriptio nal activation of cyclin D1 can oncogenically transform B-cells in con cert with a myc gene. They establish cyclin D1 as a protooncogene whos e activity appears to depend on a specific cell type as well as on a s pecific cooperating partner and link disturbances in the regulation of cell cycle progression to the development of human malignancies.