Illegitimate switch recombinations are present in approximately half of primary myeloma tumors, but do not relate to known prognostic indicators or survival

Abstract

The myeloma plasma cell is a postgerminal center, isotype-switched B cell. Chromosomal translocations into immunoglobulin heavy chain (IgH) switch regions, recombination sites in isotype switching, were initially demonstrated in myeloma cell lines but only a limited number of primary tumors. Molecular cytogenetics have since been applied to a series of primary tumors, in which IgH translocations accounted for many recurrent aberrations, among numerous nonrecurrent changes of unknown significance. This study, therefore, examined primary myeloma for IgH switch translocations using an established Southern blot assay that detected illegitimate switch recombinations. Sensitivity of the method was established by confining the analysis to 21 samples (4 stable, 17 progressive disease) with demonstrable legitimate isotype switches, of a total of 60 samples. Illegitimate recombinations were found in 12 or 57% (1 stable, 11 progressive) of 21 samples, comparable with estimates by molecular cytogenetics. The presence of switch translocations was supported by demonstrating up-regulated expression in myeloma marrow of cyclin D1 and fibroblast growth factor receptor 3 (FGFR3), candidate oncogenes on chromosomes 11q13 and 4p16, respectively. Illegitimate switches were detected most frequently in S, with more than one region involved in 6 cases. Although these results confirmed the presence of switch translocations in primary myeloma, their absence in 43% of cases may imply heterogeneity of pathogenesis. In progressive disease, there was no significant difference between patients with and without illegitimate switches in survival, nor the prognostic indicators of IntroductionMyeloma is a malignancy of the plasma cell, the terminally differentiated B cell, in which immunoglobulin genes have undergone variable region recombination, followed by isotype switching and then somatic hypermutation in the germinal center. As in other B-cell malignancies, chromosomal translocations into the immunoglobulin loci have been found. In myeloma they involve mainly the immunoglobulin heavy chain (IgH) genes on chromosome 14q32, at the switch regions upstream of each constant region gene. [1][2][3] The translocations may have occurred during the recombination of switch regions in isotype switching. Candidate oncogenes dysregulated by these translocations have been localized. [2][3][4][5][6][7][8][9] Conventional cytogenetics are relatively insensitive in the detection of switch translocations in myeloma, with an overall positivity rate of between 10% and 40%. [10][11][12] Using more sensitive molecular techniques, translocation breakpoints were initially identified in myeloma cell lines and confirmed in a limited number of primary tumors. 2,4-9 The most common partner chromosomes and their candidate oncogenes are 11q13 (cyclin D1/bcl-1), 4 4p16 (FGFR3 and MMSET or WHSC1), 5,7,9,13 6p25 (IRF4), 8 and 16q23 (c-maf ). 6 More recently, myeov and WWOX have been proposed as possible candidate genes for dysregulation on chromosomes 11 and 16, respectiv...

The enigmatic role of cyclin D1 in multiple myeloma

“…In sharp contrast with initial reports in which the amplification of cyclin D1 gene or the presence of t(11;14) were unfavorable prognostic factors [27][28][29][30] or in which the t(11;14) displays no association with the patients' survival or therapeutic response or other known parameters 4,5,31,32 the presence of cyclin D1 was more recently found a favorable parameter. Indeed, MM patients with the t(11;14) or a chromosome 11 trisomy, i.e., all expressing cyclin D1, show better overall survival, better response to intensive chemotherapy and longer duration of remission after autologous transplantations (Table II).…”

“…In MM cell lines, as well as in MM primary tumors, the breakpoints on 14q13 are coincident with switch region or JH region, indicating that errors occurred either during switch recombination or somatic hypermutation. 4,7 Chromosomal breakpoints on 14q32 are dispersed over a region of 350 kb centromeric to cyclin D1 encoding CCND1 gene (Fig. 1).…”

“…[3][4][5][6] Chromosomal translocation results in the cisactivation of candidate oncogenes located on chromosomal partners by enhancer elements within IgH genes. Several recurrent translocations likely relevant to pathogenesis, have been identified: t(11;14)(q13;q32), t(4;14)(p16;q32), t(14;16)(q32;q23), t(6;14)(p25;q32), t(6;14)(p21;q32) targeting cyclin D1/PRAD1/ BCL-1, FGFR3/MMSET, c-Maf, IRF4, cyclin D3, respectively.…”

An unusual H-Ras mutant isolated from a human multiple myeloma line leads to transformation and factor-independent cell growth

“…One possible source of such defects may be complex chromosomal aberrations frequently observed in tumor cell karyotypes. A number of studies have recently described nonrandom chromosomal translocations involving the immunoglobulin heavy chain locus as one partner and several other loci represented at varying frequencies (Bergsagel et al, 1996;Iida et al, 1997;Richelda et al, 1997;Chesi et al, 2000;Ho et al, 2001;Kuehl and Bergsagel, 2002). However, genes proximal to the translocation sites that subsequently become deregulated (i.e.…”

DNA Repair Deficiency Associated with Hematological Neoplasms

“…Genetic instability is a prominent feature of MM, since malignant plasma cells display aneuploidy and complex cytogenetics associated with poor prognosis (Calasanz et al 1997, Rajkumar et al 1999, Smadja et al 2001. Two pathways are considered important for disease progression; hyperploid MM involves trisomies of several chromosomes, whereas non-hyperploid MM is characterized by translocations in immunoglobulin heavy chain locus at 14q32 (Bergsagel and Kuehl 2005, Fonseca et al 2004, Ho et al 2001. The latter events represent aberrant class switch recombination (CSR), a process that normally alters immunoglobulin isotype with the maturation of immune response (Fenton et al 2002, Liebisch andDohner 2006).…”