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 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.
Lovec
H
H
Institut für Molekularbiologie und Tumorforschung (IMT), Philipps Universität Marburg, Germany.
Grzeschiczek
A
A
Kowalski
M B
MB
Möröy
T
T
D000818:Animals; D001402:B-Lymphocytes / Q000737:chemistry; D015415:Biomarkers / Q000032:analysis; D002471:Cell Transformation, Neoplastic; D003433:Crosses, Genetic; D019938:Cyclin D1; D016213:Cyclins / Q000032:analysis / Q000235:genetics* / Q000502:physiology; D004742:Enhancer Elements, Genetic / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D016259:Genes, myc / Q000235:genetics* / Q000502:physiology; D011905:Genes, ras / Q000235:genetics / Q000502:physiology; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D016393:Lymphoma, B-Cell / Q000737:chemistry / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D015513:Oncogene Proteins / Q000032:analysis / Q000235:genetics* / Q000502:physiology; D009928:Organ Specificity; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger / Q000032:analysis; D013950:Thymus Gland / Q000737:chemistry / Q000166:cytology; D014158:Transcription, Genetic
D015415:Biomarkers; D016213:Cyclins; D007143:Immunoglobulin Heavy Chains; C000715470:MAS1 protein, human; D015513:Oncogene Proteins; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger; D019938:Cyclin D1