title: 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.
authors.affiliation: Department of Oncology, University of Alberta and Cross Cancer Institute, Edmonton, Alberta, Canada.
authors.forename: Lorri D
authors.initials: LD
authors.lastname: Martin
authors.forename: Jana
authors.initials: J
authors.lastname: Harizanova
authors.forename: George
authors.initials: G
authors.lastname: Zhu
authors.forename: Christiaan H
authors.initials: CH
authors.lastname: Righolt
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Belch
authors.forename: Sabine
authors.initials: S
authors.lastname: Mai
authors.forename: Linda M
authors.initials: LM
authors.lastname: Pilarski
mesh_terms: D001402:B-Lymphocytes / Q000166:cytology*; D001854:Bone Marrow Cells / Q000166:cytology; D016022:Case-Control Studies; D002467:Cell Nucleus / Q000235:genetics; D019938:Cyclin D1 / Q000235:genetics; D021901:DNA, Intergenic; D056426:Genetic Loci; D006412:Hematopoietic Stem Cells / Q000473:pathology; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D017404:In Situ Hybridization, Fluorescence; D009101:Multiple Myeloma / Q000235:genetics* / Q000473:pathology*; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics; D014178:Translocation, Genetic
chemical_list: C530104:CCND1 protein, human; D021901:DNA, Intergenic; D007143:Immunoglobulin Heavy Chains; D019938:Cyclin D1; C496365:FGFR3 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3