Expression of constitutively nuclear cyclin D1 in murine lymphocytes induces B-cell lymphoma.
Mantle cell lymphoma (MCL) is a B-cell lymphoma characterized by overexpression of cyclin D1 due to the t(11;14) chromosomal translocation. While expression of cyclin D1 correlates with MCL development, expression of wild-type (WT) cyclin D1 transgene in murine lymphocytes is unable to drive B-cell lymphoma. As cyclin D1 mutants that are refractory to nuclear export display heighten oncogenicity in vitro compared with WT D1, we generated mice expressing FLAG-D1/T286A, a constitutively nuclear mutant, under the control of the immunoglobulin enhancer, Emu. D1/T286A transgenic mice universally develop a mature B-cell lymphoma. Expression of D1/T286A in B lymphocytes results in S phase entry in resting lymphocytes and increased apoptosis in spleens of young premalignant mice. Lymphoma onset correlates with perturbations in p53/MDM2/p19Arf expression and with BcL-2 overexpression suggesting that alterations in one or both of these pathways may contribute to lymphoma development. Our results describe a cyclin D1-driven model of B-cell lymphomagenesis and provide evidence that nuclear-retention of cyclin D1 is oncogenic in vivo.
Gladden
A B
AB
The Abramson Family Cancer Research Institute, Department of Cancer Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Woolery
R
R
Aggarwal
P
P
Wasik
M A
MA
Diehl
J A
JA
D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D019938:Cyclin D1 / Q000235:genetics* / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D007075:Immunoglobulin M / Q000032:analysis; D016393:Lymphoma, B-Cell / Q000235:genetics* / Q000276:immunology; D020522:Lymphoma, Mantle-Cell / Q000235:genetics* / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D016196:S Phase
D007075:Immunoglobulin M; D019938:Cyclin D1; D051358:Cyclin-Dependent Kinase 4