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 and 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 proto‐oncogene 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.

Transgenic mice expressing the Pim-1 kinase are predisposed to develop T-cell lymphomas with a long latency period of about 7-9 months. However, the exact functional basis of the oncogenic activity of Pim-1 remains obscure. C57BL/6 mice homozygous for the lpr mutation develop a well-described lymphoproliferative syndrome at about 26-30 weeks of age. This syndrome is characterized mainly by the accumulation of abnormal T cells in lymph nodes because of the lack of Fas receptor-induced apoptosis. We rind that backcross ofE.-Pim-1 transgenics (mice with a transgene that carries the mouse Pim-l gene under the transcriptional control of the immunoglobulin heavy chain gene enhancer EIs) into lpr/lpr mice results in strong acceleration of lymphoproliferation and dramatic enlargement of lymph nodes. In addition, we show here that cultured lymph node cells from E,u-Pim-1 lpr/lpr mice are rescued from rapid apoptosis that normally occurs in nontransgenic lpr cells in vitro. We also present evidence that CD4+/CD8 double-positive thymocytes from lpr/lpr mice are sensitive to dexamethasone-induced apoptosis, although lpr/lpr mice lack the Fas receptor. In contrast, E,u-Pim-1 lpr/lpr animals show considerable protection from dexamethasone-induced apoptosis. These results show that Pim-1 can strongly accelerate lymphoproliferation through inhibition of apoptosis and thereby provide first insight into the functional basis for the oncogenic activity of Pim-l.Mice homozygous for the lpr mutation show enlargement of cervical lymph nodes because of a proliferation of abnormal yet nonmalignant T cells that bear B220 and Thy-1.2 but lack CD4 and CD8 surface markers (for review, see refs. 1 and 2).