Perinucleolar relocalization and nucleolin as crucial events in the transcriptional activation of key genes in mantle cell lymphoma.
In mantle cell lymphoma (MCL), one allele of the cyclin D1 (Ccnd1) gene is translocated from its normal localization on chromosome 11 to chromosome 14. This is considered as the crucial event in the transformation process of a normal naive B-cell; however, the actual molecular mechanism leading to Ccnd1 activation remains to be deciphered. Using a combination of three-dimensional and immuno-fluorescence in situ hybridization experiments, the radial position of the 2 Ccnd1 alleles was investigated in MCL-derived cell lines and malignant cells from affected patients. The translocated Ccnd1 allele was observed significantly more distant from the nuclear membrane than its nontranslocated counterpart, with a very high proportion of IgH-Ccnd1 chromosomal segments localized next to a nucleolus. These perinucleolar areas were found to contain active RNA polymerase II (PolII) clusters. Nucleoli are rich in nucleolin, a potent transcription factor that we found to bind sites within the Ccnd1 gene specifically in MCL cells and to activate Ccnd1 transcription. We propose that the Ccnd1 transcriptional activation in MCL cells relates to the repositioning of the rearranged IgH-Ccnd1-carrying chromosomal segment in a nuclear territory with abundant nucleolin and active PolII molecules. Similar transforming events could occur in Burkitt and other B-cell lymphomas.
Unité Mixte de Recherche 8126, Université Paris-Sud, National Centre for Scientific Research, Institut de Cancérologie Gustave Roussy, Villejuif, France;
Jeanne
J
Allinne
Andrei
A
Pichugin
Olga
O
Iarovaia
Manel
M
Klibi
Ana
A
Barat
Ewa
E
Zlotek-Zlotkiewicz
Diana
D
Markozashvili
Natalia
N
Petrova
Valérie
V
Camara-Clayette
Elena
E
Ioudinkova
Joëlle
J
Wiels
Sergey V
SV
Razin
Vincent
V
Ribrag
Marc
M
Lipinski
Yegor S
YS
Vassetzky
D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000076246:CCCTC-Binding Factor; D045744:Cell Line, Tumor; D002466:Cell Nucleolus / Q000378:metabolism*; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D052138:Genes, Neoplasm; D006367:HeLa Cells; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000235:genetics*; D010750:Phosphoproteins / Q000378:metabolism*; D021381:Protein Transport; D016601:RNA-Binding Proteins / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D015533:Transcriptional Activation; D000097796:Nucleolin
D000076246:CCCTC-Binding Factor; D019938:Cyclin D1; D010750:Phosphoproteins; D016601:RNA-Binding Proteins; D012097:Repressor Proteins; D000097796:Nucleolin; C000619697:CTCF protein, human