A myeloma translocation-like model associating CCND1 with the immunoglobulin heavy-chain locus 3' enhancers does not promote by itself B-cell malignancies.
Cyclin D1 overexpression is associated with mantle cell lymphoma and multiple myeloma. In myeloma, it often results from chromosomal translocations linking the CCND1 gene to the 3' part of the IgH locus constant region. This region includes a single and potent transcriptional regulatory region (RR) 3' of the Calpha gene mostly active in mature B-cells. To check whether this RR alone was sufficient to deregulate CCND1, we generated mice carrying a 3'IgH RR-driven human CCND1 transgene and specifically up-regulating cyclin D1 expression in B-cells. In transgenic B-cells, cyclin D1 enforced cell cycle entry in response to various stimuli (LPS, anti-IgM, anti-CD40) but also increased cell death, so that exaggerated proliferation did not result in peripheral lymphocytosis. Despite exaggerated B-cell entry into G(1) phase, malignant lymphoproliferation did not occur either. Crossing of CCND1-3'IgH RR mice with c-myc-3'IgH RR mice did not reveal accelerated tumorigenesis as compared with c-myc-3'IgH RR mice alone. The data presented here demonstrate that the 3'IgH RR-mediated deregulation of CCND1 in mature B-cells cannot by itself trigger the development of lymphomas and strengthen the concept that cyclin D1 per se is not an armful proto-oncogene. Rather its overexpression in several malignancies might be only a stigma of lymphomagenesis or represent a single hit within a multiple hit process.
Fiancette
Rémi
R
UMR CNRS 6101, Centre National de la Recherche Scientifique, Université de Limoges, 2 rue Dr. Marcland, 87025 Limoges, France.
Amin
Rada
R
Truffinet
Véronique
V
Vincent-Fabert
Christelle
C
Cogné
Nadine
N
Cogné
Michel
M
Denizot
Yves
Y
D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000378:metabolism* / Q000473:pathology*; D015153:Blotting, Western; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000502:physiology*; D004195:Disease Models, Animal; D005434:Flow Cytometry; D005822:Genetic Vectors; D007124:Immunoenzyme Techniques; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000166:cytology / Q000378:metabolism
C530104:CCND1 protein, human; D007143:Immunoglobulin Heavy Chains; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger; D019938:Cyclin D1