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Allinne J.,University Paris - Sud | Pichugin A.,University Paris - Sud | Pichugin A.,Lia1066 Laboratoire Franco Russe Of Recherche En Oncologie | Iarovaia O.,University Paris - Sud | And 26 more authors.
Blood | Year: 2014

Inmantle cell lymphoma (MCL), one allele of the cyclinD1 (Ccnd1) geneis 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. © 2014 by The American Society of Hematology.

Markozashvili D.,University Paris - Sud | Markozashvili D.,Lia1066 Laboratoire Franco Russe Of Recherche En Oncologie | Ribrag V.,Institute Of Recherche Integree En Cancerologie Irciv | Ribrag V.,University Paris - Sud | And 2 more authors.
Investigational New Drugs | Year: 2015

A vast majority of lymphomas and leukaemias are results of translocations. These translocations produce various genetic and epigenetic changes that lead to oncogenesis. This opens an opportunity to use a relatively new class of anti-cancer agents, inhibitors of histone deacetylases (HDACi) to target lymphoid malignancies. Surprisingly, the rational basis for treatment of lymphomas with HDACi is far from clear, although some positive results have been obtained. Here we analyze the effect of histone deacetylase (HDAC) inhibitors on lymphoid malignancies. © 2015 Springer Science+Business Media New York.

Iarovaia O.V.,Russian Academy of Sciences | Rubtsov M.,Lia1066 Laboratoire Franco Russe Of Recherche En Oncologie | Rubtsov M.,Moscow State University | Ioudinkova E.,Russian Academy of Sciences | And 7 more authors.
Molecular Cancer | Year: 2014

Chromosomal translocations are a major cause of cancer. At the same time, the mechanisms that lead to specific chromosomal translocations that associate different gene regions remain largely unknown. Translocations are induced by double strand breaks (DSBs) in DNA. Here we review recent data on the mechanisms of generation, mobility and repair of DSBs and stress the importance of the nuclear organization in this process. © 2014 Iarovaia et al.; licensee BioMed Central Ltd. This article is published under license to BioMed Central Ltd.

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