Dynamic chromosomal rearrangements in Hodgkin's lymphoma are due to ongoing three-dimensional nuclear remodeling and breakage-bridge-fusion cycles (original) (raw)
Related papers
Conservation of Relative Chromosome Positioning in Normal and Cancer Cells
Current Biology, 2002
pate in recurring translocations have a tendency to be in close proximity to each other before the translocation event. We tested this prediction by analyzing the relative The AT-13 cell line is derived from a T cell lymphoma in an ATM Ϫ/Ϫ mouse and has been cytogenetically characterized by spectral karyotyping to contain two translocations involving chromosomes 12, 14, and 15 (Figure Summary 1A; [15]). The cell line displays chromosome abnormalities T(12;14), T(Is(15;14);Dp15) and Del(14) [16]. To probe Chromosomes exist in the interphase nucleus as indithe position of the rearranged chromosomes in invidual chromosome territories. It is unclear to what terphase AT-13 cells, we used chromosome-painting extent chromosome territories occupy particular posiprobes specific for chromosomes 12, 14, and 15 to pertions with respect to each other and how structural form FISH (Figure 1B). As expected, in the majority of rearrangements, such as translocations, affect chro-AT-13 cells double color signals corresponding to chromosome organization within the cell nucleus. Here we mosome translocations 12:14 (henceforth referred to as analyze the relative interphase positioning of chromo-T12) and 14:15 (T14) as well as additional single signals somes in mouse lymphoma cells compared to normal corresponding to the normal chromosome 12, the del14, splenocytes. We show that in a lymphoma cell line and two chromosomes 15 were observed (Figure 1B). derived from an ATM Ϫ/Ϫ mouse, two translocated
Interphase Chromosome Behavior in Normal and Diseased Cells
SpringerLink, 2013
Interphase chromosomes are nonrandomly positioned in the nuclei of normal cells. They occupy specifi c locations with respect to a radial distribution from the nuclear edge to the nuclear interior. Furthermore, there is some evidence that interphase chromosomes reproducibly have the same neighbors that can be involved in creating translocations which lead to cancer. Not only are chromosomes nonrandomly positioned but they are anchored to certain regions of the cell nucleus by cellular structures such as the nuclear lamina and the nucleolus. Global screening of the genome has identifi ed both lamina-associated domains and nucleolarassociated domains. Increasingly, researchers are fi nding that interphase chromosomes are mislocalized in disease situations. The consequences of chromosome mislocalization are not yet that clear, but gene expression can be affected with interphase chromosomes being located in another compartment of the nucleus, changing
Human Genetics, 1982
In 1885 Carl Rabl published his theory on the internal structure of the interphase nucleus. We have tested two predictions of this theory in fibroblasts grown in vitro from a female Chinese hamster, namely (1) the Rabl-orientation ofinterphase chromosomes and (2) the stability of the chromosome arrangement established in telophase throughout the subsequent interphase. Tests were carried out by premature chromosome condensation (PCC) and laser-UV-microirradiation of the interphase nucleus. Rabl-orientation of chromosomes was observed in G1 PCCs and G2 PCCs. The cell nucleus was microirradiated in G1 at one or two sites and pulse-labelled with SH-thymidine for 2 h. Cells were processed for autoradiography either immediately thereafter or after an additional growth period of 10 to 60h. Autoradiographs show unscheduled DNA synthesis (UDS) in the microirradiated nuclear part(s). The distribution of labelled chromatin was evaluated in autoradiographs from 1035 cells after microirradiation of a single nuclear site and from 253 cells after microirradiation of two sites. After 30 to 60 h postincubation the labelled regions still appeared coherent although the average size of the labelled nuclear area fr increased from 14.2% (0 h) to 26.5% (60 h). The relative distance dr, i.e. the distance between two microirradiated sites divided by the diameter of the whole nucleus, showed a slight decrease with increasing incubation time. Nine metaphase figures were evaluated for UDS-label after microirradiation of the nuclear edge in GI. An average of 4.3 chromosomes per cell were labelled. Several chromosomes showed joint labelling of both distal chromosome arms including the telomeres, while the centromeric region was free from label. This label pattern is interpreted as the result of a V-shaped orientation of these particular chromosomes in the interphase nucleus with their telomeric regions close to each other at the nuclear edge. Our data support the tested predictions of the RaN-model. Small time-dependent changes of the nuclear space 4 Part of this work is included in the doctoral thesis of H. Baumann to be submitted to the Faculty of Biology of the University of Heidelberg 5 Part of this work is included in the doctoraI thesis of V. Teuber to be submitted to the Faculty of Medicine of the University of Freiburg i. Br. Offprint requests to: T. Cremer occupied by single chromosomes and of their relative positions in the interphase nucleus seem possible, while the territorial organization of interphase chromosomes and their arrangement in general is maintained during interphase. The present limitations of the methods used for this study are discussed.
Experimental Cell Research, 1989
Double in situ hybridization with mercurated and biotinylated chromosome specific DNA probes in combination with digital image analysis provides a new approach to compare the distribution of homologous and nonhomologous chromosome targets within individual interphase nuclei. Here we have used two DNA probes representing tandemly repeated sequences specific for the constitutive heterochromatin of the human chromosomes 1 and 15, respectively, and studied the relative arrangements of these chromosome targets in interphase nuclei of human lymphocytes, amniotic fluid cells, and fibroblasts, cultivated in vitro. We have developed a ZD-image analysis approach which allows the rapid evaluation of large numbers of interphase nuclei. Models to test for a random versus nonrandom distribution of chromosome segments are discussed taking into account the three-dimensional origin of the evaluated 2D-distribution. In all three human diploid cell types the measurements of target-target and target-center distances in the ZD-nuclear image revealed that the labeled segments of the two chromosomes 15 were distributed both significantly closer to each other and closer to the center of the nuclear image than the labeled chromosome 1 segments. This result can be explained by the association of nucleolus organizer regions on the short arm of chromosome 15 with nucleoli located more centrally in these nuclei and does not provide evidence for a homologous association per se. In contrast, evaluation of the interphase positioning of the two chromosome 1 segments fits the random expectation in amniotic fluid and fibroblast cells, while in experiments using lymphocytes a slight excess of larger distances between these homologous targets was occasionally observed. 2D-distances between the labeled chromosome 1 and 15 segments showed a large variability in their relative positioning. In conclusion our data do not support the idea of a strict and permanent association of these homologous and nonhomologous targets in the cell types studied so far. @ 1989 Academic RCSS, Inc. Cell type specific chromatin arrangements in interphase nuclei may reflect processes of cellular differentiation and cell specific gene expression [l-4]. So far the methodology has been lacking to put this hypothesis to rigorous ' To whom reprint requests should be addressed.
Chromosome spatial clustering inferred from radiogenic aberrations
International Journal of Radiation Biology, 2004
Purpose: Analysing chromosome aberrations induced by low linear energy transfer (LET) radiation in order to characterize systematic spatial clustering among the 22 human autosomes in human lymphocytes and to compare their relative participation in interchanges. Materials and methods: A multicolour fluorescence in situ hybridization (mFISH) data set, specifying colour junctions in metaphases of human peripheral blood lymphocytes 72 h after in vitro exposure to low LET radiation, was analysed separately and in combination with previously published results. Monte Carlo computer simulations and mathematical modelling guided data analysis. Results and conclusions: Statistical tests on aberration data confirmed two clusters of chromosomes, {1, 16, 17, 19, 22} and {13, 14, 15, 21, 22}, as having their members being on average closer to each other than randomness would predict. The first set has been reported previously to be near the centre of the interphase nucleus and to be formed mainly by gene-rich chromosomes, while the second set comprises the nucleolus chromosomes. The results suggest a possible interplay between chromosome positioning and transcription. A number of other clusters suggested in the literature were not confirmed and considerable randomness of chromosome-chromosome juxtapositions was present. In addition, and consistent with previous results, it was found that chromosome participation in interchanges is approximately proportional to the two-thirds power of the DNA content.
Cytometry Part A, 2011
Chromosome positions within the nucleus of mammalian cells are nonrandom and it is assumed that chromosomal neighborhoods affect the probability of translocations. Four chromosomes can be involved in c-myc-activating chromosomal translocations in mouse plasmacytoma (PCT): the c-myc gene on mouse chromosome 15 can be juxtaposed to either one of the immunoglobulin (Ig) loci on chromosomes 12 (IgH), 16 (Igk), or 6 (Igj). In the BALB/c mouse, the translocation between chromosomes 12 and 15, T(12;15), is most common (90%) while the other two possible translocations, T(6;15) and T(16;15), are much less common (\10%). In contrast, in the BALB/ cRb6.15 mouse, T(6;15) is found with the same frequency as T(12;15). We, therefore, examined the distance between chromosomes 15 and 12, 6, and 16 in primary mouse B lymphocytes in order to examine the effect of the chromosome proximity on the translocation frequency. We performed three-dimensional fluorescent in situ hybridization (3D-FISH) with chromosome paints. We acquired three-dimensional image stacks with 90 slices per stack and used constrained iterative deconvolution. The nucleus and chromosomes were segmented from this image stack and the interchromosomal distances were measured. Chromosomes 6 and 15 were found in close proximity in BALB/ cRb6.15 mice (82%), whereas they did not share this neighborhood relationship in BALB/c mice. No other chromosome combinations showed such a high percentage of close proximities in either mouse strain. Chromosome positions contribute to translocation frequencies in mouse PCTs. The BALB/cRb6.15 mouse data argue for a proximity relationship of chromosomes that engage in illegitimate recombination. These positions are not, however, the only contributing factor as the T(12;15) translocation preference in BALB/c mice could not be supported by significantly elevated proximity of chromosomes 12 and 15 versus 12 and 16 or 12 and 6. Moreover, while there is a significant increase in T(6;15) in BALB/cRb6.15 mice, T(12;15) still occurs in this mouse strain. ' 2011 International Society for Advancement of Cytometry