GENES, CHROMOSOMES & CANCER 52:523–537 (2013) Differential Nuclear Organization of Translocation-Prone Genes in Nonmalignant B Cells from Patients with t(14;16) as Compared with t(4;14) or t(11;14) Myeloma Lorri D. Martin, 1 Jana Harizanova, 2,3 Christiaan H. Righolt, 2,4 George Zhu, 1 Sabine Mai, 2 Andrew R. Belch, 1 and Linda M. Pilarski 1 * 1 Department of Oncology,University of Alberta and Cross Cancer Institute, Edmonton, Alberta,Canada 2 Manitoba Institute of Cell Biology,CancerCare Manitoba,University of Manitoba,Winnipeg, Manitoba,Canada 3 Department of Systemic Cell Biology, Max-Planck Institute of Molecular Physiology, Dortmund,Germany 4 Department of Imaging Science and Technology, Delft University of Technology, Delft,The Netherlands Gene organization in nonmalignant B cells from t(4;14) and t(11;14) multiple myeloma (MM) patients differs from that of healthy donors. Among recurrent IGH translocations in MM, the frequency of t(4;14) (IGH and FGFR3) or t(11;14) (IGH and CCND1) is greater than the frequency of t(14;16) (IGH and MAF). Gene organization in t(14;16) patients may influence translocation potential of MAF with IGH. In patients, three-dimensional FISH revealed the positions of IGH, CCND1, FGFR3, and MAF in nonmalignant B cells that are likely similar to those when MM first arose, compared with B cells from healthy donors. Overall, IGH occupies a more central nuclear position while MAF is more peripherally located. However, for B cells from t(4;14) and t(11;14) patients, IGH and FGFR3, or IGH and CCND1 are found in spatial proximity: IGH and MAF are not. This differs in B cells from t(14;16) patients and healthy donors where IGH is approximately equidistant to FGFR3, CCND1, and MAF , suggesting that gene organization in t(14;16) patients is different from that in t(4;14) or t(11;14) patients. Translocations between IGH and MAF may arise only in the absence of close proximity to the more frequent partners, as appears to be the case for individuals who develop t(14;16) MM. V V C 2013 Wiley Periodicals, Inc. INTRODUCTION Multiple myeloma (MM) is a B-lineage malig- nancy characterized by extensive karyotypic instability, including chromosomal translocations (Debes-Marun et al., 2003, 2005, 2012). The translocations most frequently involve the IGH locus at 14q32, as for many B cell malignancies (Fabris et al., 2005; Liebisch and Dohner, 2006). Although most other B cell malignancies harbour a single, specific IGH translocation partner, MM displays a promiscuity of recurrent translocation partners with IGH. These include: CCND1 t(11;14)(q13;q32); FGFR3 t(4;14)(p16;q32); and MAF t(14;16)(p16;q32). Evidence (Ghosh and Matsui, 2009; Basak and Carrier, 2010) suggests that the myeloma precursor arises from a post- germinal center CD19þ B cell, including findings by two groups that CD19þ B cells isolated from the peripheral blood of MM patients were able to recapitulate the disease in NOD/SCID mice or in culture (Pilarski et al., 2002; Kirshner et al., 2008; Matsui et al., 2008). Although it is not possible to precisely identify the nonmalignant B cells that accumulate genetic abnormalities and ultimately transform to a MM progenitor, the clonal reper- toire in MM patients reflects that in normal B cells making it reasonable to speculate that the cancer arises from normal B cells. Previous work demonstrates the presence of IGH translocations in B cells isolated from patient peripheral blood (Debes-Marun et al., 2005), and may be a pri- mary event in myelomagenesis (Gabrea et al., 2006; Basak and Carrier, 2010). Recurrent translo- cations occur with different frequencies: t(11;14)—20%; t(4;14)—15-20%; and t(14;16)— 5% (Bergsagel and Kuehl, 2005). The mechanisms of locus selection during translocation is poorly understood; it is known, Supported by: Canadian Institutes of Health Research, the Alberta Cancer Foundation, Myeloma Alberta Support Group, Alberta Heritage Foundation for Medical Research Graduate Studentship (to L.D.M.), and Susan Komen Foundation for Breast Cancer (to J.H.). *Correspondence to: Linda M. Pilarski, Department of Oncology, University of Alberta and Cross Cancer Institute, 11560 University Ave., Edmonton, AB, Canada T6G1Z2. E-mail: lpilarsk@ualberta.ca Received 27 June 2012; Accepted 8 January 2013 DOI 10.1002/gcc.22049 Published online 5 March 2013 in Wiley Online Library (wileyonlinelibrary.com). RESEARCH ARTICLES V V C 2013 Wiley Periodicals, Inc.