Large-scale nuclear remodeling and transcriptional deregulation occur on both derivative chromosomes after Mantle Cell Lymphoma chromosomal translocation

Abstract

ABSTRACTRecurrent chromosomal translocations are found in many blood and solid cancers. Balanced translocations, frequent in lymphoid malignancies, lead to the formation of two aberrant derivative (der) chromosomes. This event often leads to overexpression of an oncogene. In many cases, the expression of an oncogene is not enough to produce a malignant phenotype; however, most part of the studies focus on the events involving the chromosome where the oncogene is located, but rarely the other der chromosome where other oncogenic alterations may potentially arise. Mantle cell lymphoma (MCL), an aggressive B-cell non-Hodgkin lymphoma, is a perfect example of this. In 85% of the cases, it is characterized by the translocation t(11;14), which leads to the overexpression of cyclin D1 (CCND1) gene which results juxtaposed to the immunoglobulin heavy chain (IGH) gene on the der14 chromosome. This feature alone is not sufficient to induce oncogenesis. Here we focused on the der11 chromosome. We demonstrated that expression of 88 genes located in a 15mb region close to the translocation breakpoint on the der11 was deregulated both in the GRANTA-519 MCL cell line and in B-cells from MCL patients. We found that a large segment of der11containing deregulated genes was relocated from its normal position in the nuclear periphery towards the center of the nucleus in close proximity to the nucleolus where the abundant nucleolar protein nucleolin binds a subset of genes located close to the breakpoint and activates their expression. This finding allowed to identify new potential oncogenes involved in MCL and the mechanisms of their upregulation.