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

Abstract

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.

Depletion of lamins B1 and B2 promotes chromatin mobility and induces differential gene expression by a mesoscale-motion-dependent mechanism

“…To assess the effect of B-type lamin degradation on chromosome-specific loci in live HCT116 LMN(B1&B2)−AID cells, we labeled genomic regions on chromosomes 3 and 19 using CRISPR-Sirius [55]. Chromosomes 3 and 19 were chosen to represent chromosomes that are localized relatively near the nuclear periphery and the nuclear interior, respectively [55][56][57][58][59][60]. Specifically, we chose one intronic gene region on Chromosome 3 (XXYLT1) containing ~ 333 endogenous tandem repeats, and one intronic gene region on Chromosome 19 (TCF3) containing ~ 36 endogenous tandem repeats as a reference to the nuclear interior.…”

Mechanisms associated with t(7;12) acute myeloid leukaemia: from genetics to potential treatment targets

“…In the nuclei of healthy lymphocytes, MNX1 is localised at the periphery, and ETV6 is normally localised in the nuclear interior, therefore the repositioning of MNX1 into a transcriptionally active (internal) region due to the t(7;12) has been suggested to trigger its expression. Nuclear genome re-organisation due to the chromosomal abnormalities has been shown to affect gene regulation [ 67 , 68 ]; however, it remains unclear whether MNX1 ectopic expression is a cause or an effect of the nuclear reorganisation. Interestingly, previous nuclear localisation analysis also showed that MNX1 becomes transcriptionally active during neuronal differentiation of the neuroblastoma SK-N-BE cell line, and this activity is correlated with its relocation towards the nuclear interior [ 61 ].…”

Circular and Fusion RNAs in Medulloblastoma Development

“…In tumor tissues, it is well-known that chromosomal rearrangements can drive tumor growth [41,42]. Therefore, the fusions observed in medulloblastoma may result from such events.…”