Chromosome Territories in Hematological Malignancies

Abstract

Chromosomes are organized in distinct nuclear areas designated as chromosome territories (CT). The structural formation of CT is a consequence of chromatin packaging and organization that ultimately affects cell function. Chromosome positioning can identify structural signatures of genomic organization, especially for diseases where changes in gene expression contribute to a given phenotype. The study of CT in hematological diseases revealed chromosome position as an important factor for specific chromosome translocations. In this review, we highlight the history of CT theory, current knowledge on possible clinical applications of CT analysis, and the impact of CT in the development of hematological neoplasia such as multiple myeloma, leukemia, and lymphomas. Accumulating data on nuclear architecture in cancer allow one to propose the three-dimensional nuclear genomic landscape as a novel cancer biomarker for the future.

Keywords: chromosome territories; differentiation; genome markers; leukemia; lymphoma; multiple myeloma; nuclear architecture; nuclear organization.

Figure 1

History of chromosome territories. In 1885, Carl Rabl alluded to what nowadays is termed chromosome territories. In 1905 and 1909, the chromosome territories concept was established based on studies in plant cells as well as horse roundworms and other organisms. In 1973, the chromosome territories were disclaimed by experiments using electron microscopy, marking the belief that chromatin would freely intermingle like a bowl of spaghetti. In 1977, the first concrete experimental evidence came to support the chromosome territories theory with Stack’s experiments. In 1988, the first visualization of a territorial-like organization of chromosomes was possible using the fluorescence in situ hybridization (FISH) technique. In 1998, the chromosome territories could be followed in vivo for a few minutes using live cell analysis (represented by the clock in the figure). Finally, with the association of chromosome probes, 3D-FISH protocols, confocal microscopy, and 3D image analysis, all chromosome territories could be studied in detail and in the same cell for the first time in 2005 [50]. For additional details and references, see text.

Figure 2

Chromosome territories: established concepts. Overview of chromosome organization regarding different proposed models of CT etiology. The non-random chromosome organization varies according to the cellular differentiation status, nuclear shape, nucleolar-associated chromosomes, chromosome size, gene density, and cell type. Chromosome spatial organization is emerging as an important mechanism of gene expression regulation and key determinant of cell fate. Image inspired by hallmarks of cancer, 2011 [72].

Figure 3

The role of chromosome territories in multiple myeloma (MM). Correlation of chromosome position and chromatin state as drivers of the malignant progression in MM. For details, please see Section 3.1. In MM, some chromosomes display altered positions, towards the nuclear center, compared to regular B lymphocytes. Some chromosome territory volumes also increase in MM, and changes in nuclear organization may favor MM progression by modulating gene expression.