Promiscuous translocations into immunoglobulin heavy chain switch regions in multiple myeloma

Abstract

In multiple myeloma, karyotypic 14q32 translocations have been identified at a variable frequency (10-60% in different studies). In the majority of cases, the partner chromosome has not been identified (14q؉), and in the remaining cases, a diverse array of chromosomal partners has been implicated, with 11q13 being the most common. We developed a comprehensive Southern blot assay to identify and distinguish different kinds of immunoglobulin heavy chain (IgH) switch recombination events. Illegitimate switch recombination fragments (defined as containing sequences from only one switch region) are potential markers of translocation events into IgH switch regions and were identified in 15 of 21 myeloma cell lines, including seven of eight karyotyped lines that have no detectable 14q32 translocation. From all nine lines or tumor samples analyzed further, cloned illegitimate switch recombination fragments were confirmed to be IgH switch translocation breakpoints. In three of these cases, the translocation breakpoint was shown to be present in the primary tumor. These translocation breakpoints involve six chromosomal loci: 4p16.3 (two lines and the one tumor); 6; 8q24.13; 11q13.3 (in three lines); 16q23.1; and 21q22.1. We suggest that translocations into the IgH locus (i) are frequent (karyotypic 14q32 translocations and͞or illegitimate switch recombination fragments are present in primary tumor samples and in 19 of 21 lines that we have analyzed); (ii) occur mainly in switch regions; and (iii) involve a diverse but nonrandom array (i.e., frequently 11q13 or 4p16) of chromosomal partners. This appears to be the most frequent genetic abnormality in multiple myeloma.

Expression of PTEN in PTEN-deficient multiple myeloma cells abolishes tumor growth in vivo

“…Some associative correlations have been described, such as non-random chromosomal translocations (Bergsagel et al, 1996;Richelda et al, 1997;Gabrea et al, 1999), but direct demonstration of a role in malignancy for genes near these sites has been elusive. Similarly, mutations in genes frequently observed in other cancers such as p53 and Ras (Portier et al, 1992;Yasuga et al, 1995) have not been consistently observed in myeloma.…”

“…the Bcl-2 translocation in CML), such lesions have not been identi®ed in MM. During the past few years, a number of translocations have been described in MM such as those involving the immunoglobulin locus and a non-random chromosomal partner (Bergsagel et al, 1996;Richelda et al, 1997). However, the biological signi®cance of such translocations has yet to be determined.…”

Analysis of MUM1/IRF4 Protein Expression Using Tissue Microarrays and Immunohistochemistry

“…Chromosomal translocations involving the immunoglobulin heavy-chain (IgH) locus on chromosome 14 (14q32) are detected in Ն60% of cases of multiple myeloma (1)(2)(3). Partner chromosome loci and genes participating in these translocations involving the IgH region are largely uncharacterized.…”

Nonrandom 4p13 rearrangements of the RhoH/TTF gene, encoding a GTP-binding protein, in non-Hodgkin's lymphoma and multiple myeloma

“…MM is frequently associated with chromosome abnormalities, especially translocations involving 14q32 and a variety of other chromosomes, including the short arm of chromosome 4 (Zandecki et al, 1996;Bergsagel et al, 1996). One case of t(4;14) was already described in MM, but with a breakpoint in the 4p16.3 region, implicating the FGFR3 gene, which was shown to be deregulated by juxtaposition to the IgH gene, in this observation (Chesi et al, 1997).…”