Differential positioning and close spatial proximity of translocation‐prone genes in nonmalignant B‐cells from multiple myeloma patients

Abstract

Accumulating evidence suggests that spatial proximity of potential chromosomal translocation partners influences translocation probability. It is not known, however, whether genome organization differs in nonmalignant cells from patients as compared to their cellular counterparts from healthy donors. This could contribute to translocation potential causing cancer. Multiple myeloma is a hematopoietic cancer of the B‐lineage, characterized by karyotypic instability, including chromosomal translocations involving the IGH locus and several translocation partners. Utilizing 3‐D FISH and confocal imaging, we investigate whether nuclear spatial positioning of the translocation‐prone gene loci, IGH, FGFR3, and CCND1 differs in nonmalignant cell subsets from multiple myeloma patients as compared to positioning in their corresponding healthy donor cell subsets. 3‐D analysis software was used to determine the spatial proximity of potential translocation pairs and the radial distribution of each gene. We observed that in all cell subsets, the translocation‐prone gene loci are intermediately located in the nucleus, while a control locus occupies a more peripheral position. In nonmalignant B‐cells from multiple myeloma patients, however, the translocation‐prone gene loci display a more central nuclear position and close spatial proximity. Our results demonstrate that gene positioning in nonmalignant B‐cells from multiple myeloma patients differs from that in healthy donors, potentially contributing to translocation probability in patient cells. We speculate that genome reorganization in patient B‐cells may closely reflect gene positioning at the time the multiple myeloma‐specific translocation initially formed, thus influencing translocation probability between proximal loci in the B‐cell population from which the malignancy emerged. © 2012 Wiley Periodicals, Inc.

MiRNome expression is deregulated in the peripheral lymphoid compartment of multiple myeloma

“…In a recent study, Martin et al (), showed that genome organization in MM patients differs in non‐malignant cells as compared to their cellular counterparts in healthy blood donors. This suggests that variances in genome structure may contribute to its destabilization, aberration and the modification of total transcription activities, resulting in the possibility of causing cancer.…”

FGFR3 preferentially colocalizes with IGH in the interphase nucleus of multiple myeloma patient B‐cells when FGFR3 is located outside of CT4

“…To identify patients with plasma cells positive for IGH translocations, conventional FISH was used. This typical 2D fixation method has been described previously (Martin et al, ) and results in a 2D (flattened) cell adhesion to slide. Four commercial probe sets were used for each bone marrow sample: LSI IGH dual color break apart probe for the detection of chromosome breakage at the 14q32 locus; and three LSI dual color, dual fusion probes: IGH / FGFR3 for the detection of t(4;14)(p16;q32); IGH / CCND1 for the detection of t(11;14)(q13;q32), and IGH / MAF for the detection of t(14;16)(q32;q23).…”

“…Most studies of genome organization with respect to translocation potential have utilized cells from healthy donors; the assumption being that genome positioning in cells from healthy donors does not differ from positioning in non‐translocated cells from affected patients. We have previously provided evidence that IGH and FGFR3 , and not IGH and MAF , are closer together in the interphase nucleus of non‐malignant B‐cells from MM patients than in B‐cells from healthy donors, suggesting an increased translocation potential in the patient‐derived cells (Martin et al, ; Martin et al, ). We sought to investigate the idea that extra‐territorial positioning of translocation‐prone gene loci may influence translocation potential in B‐cells from healthy donors and in non‐malignant B cells from patients.…”

“…Moreover, gene loci demonstrate non‐random positioning patterns (Roix et al, ; Bolzer et al, ; Martin et al, ), and gene positioning can vary according to transcriptional status (Osborne et al, ; Osborne et al, ). Additional studies provide compelling evidence that extra‐territorial positioning of specific genes is a contributing factor to gene regulation, as genes that “loop out” of their respective CTs are actively transcribed (Volpi et al, ; Williams et al, ; Chambeyron and Bickmore, ; Osborne et al, ), a finding in accord with the model described above.…”

“…Spatial proximity of genetic loci in the interphase nucleus correlates with chromosome translocation frequency (Neves et al, 1999;Roix et al, 2003;Gandhi et al, 2009;Martin et al, 2012), as proximal genes are more likely to participate in a translocation event than those which are distal. Spatial proximity of translocation partners varies in different tissues, and at different stages of differentiation (Neves et al, 1999;Nikiforova et al, 2000;Parada et al, 2004b;Martin et al, 2012;Martin et al, 2013).…”