Chromosomal Rearrangements and Altered Nuclear Organization: Recent Mechanistic Models in Cancer.

Abstract

Simple SummaryNew methodologies and technologies developed in the last few decades have highlighted the precise spatial organization of the genome into the cell nucleus, with chromatin architecture playing a central role in controlling several genome functions. Genes are expressed in a well-defined way and at a well-defined time during cell differentiation, and alterations in genome organization can lead to genetic diseases, such as cancers. Here we review how the genome is organized in the cell nucleus and the evidence of genome misorganization leading to cancer diseases.The last decade has seen significant progress in understanding how the genome is organized spatially within interphase nuclei. Recent analyses have confirmed earlier molecular cytogenetic studies on chromosome positioning within interphase nuclei and provided new information about the topologically associated domains (TADs). Examining the nuances of how genomes are organized within interphase nuclei will provide information fundamental to understanding gene regulation and expression in health and disease. Indeed, the radial spatial positioning of individual gene loci within nuclei has been associated with up- and down-regulation of specific genes, and disruption of normal genome organization within nuclei will result in compromised cellular health. In cancer cells, where reorganization of the nuclear architecture may occur in the presence of chromosomal rearrangements such as translocations, inversions, or deletions, gene repositioning can change their expression. To date, very few studies have focused on radial gene positioning and the correlation to gene expression in cancers. Further investigations would improve our understanding of the biological mechanisms at the basis of cancer and, in particular, in leukemia initiation and progression, especially in those cases where the molecular consequences of chromosomal rearrangements are still unclear. In this review, we summarize the main milestones in the field of genome organization in the nucleus and the alterations to this organization that can lead to cancer diseases.