Large-scale chromatin remodelling and transcriptional deregulation on der11 following translocation in Mantle Cell Lymphoma

Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin lymphoma characterized by poor prognosis and survival rate. Its genetic hallmark is the translocation t(11;14) which leads to the overexpression of cyclin D1 (CCND1) gene which becomes juxtaposed to the immunoglobulin heavy chain (IGH) gene on the newly formed der14 chromosome. This recurrent feature is however not sufficient to promote the development of the disease as expression of CCND1 under different known IgH enhancers in transgenic mice is not sufficient for tumor development. Additional alterations are necessary to develop a malignant phenotype. When a translocation occurs, it can induce overall nuclear reorganization, epigenetic changes and altered gene expression that may contribute to oncogenesis. Here we investigated changes in nuclear positioning of gene loci and their transcription after the t(11;14) focusing our attention on the events occurring on the der11 chromosome. Methods. 3D-immunoFISH and image analysis software were used to analyze gene loci position in nuclear space. To analyze changes of transcriptional level of genes located on the der11, quantitative RT-PCR, bioinformatic analysis and data mining were performed. ChIP was carried out to analyze specific interactions between nucleolin and the genome in MCL. Results. We demonstrated that the expression of many genes located close to the translocation breakpoint was deregulated in MCL compared to other lymphomas and to B-cells from healthy donors. Most of these genes were located on the der11 after the t(11;14). We found that the der11 is relocated in close proximity to the nucleolus. Here the nucleolin, that is part of the transcriptional factor LR-1 can deregulate gene expression by direct binding to promoters. We found that the LR-1 consensus sequence and the nucleolin binding sites are significantly enriched in the regions covered by the deregulated genes compared to the rest of chromosme11 and to cells without the t(11;14). Conclusions. We identified new epigenetic events that contribute to MCL development following t(11;14).