Reciprocal translocations involving the IgH locus (14q32) appear to provide an early transformation event in most multiple myeloma (MM) tumors. These primary translocations are targeted to V/D/J sequences due to errors in VDJ recombination or somatic hypermutation, or to IgH switch regions due to errors in switch recombination. The translocations include a promiscuous array of at least 20 nonrandom chromosomal partners, each including an oncogene that is dysregulated by juxtaposition to potent IgH enhancers. The most frequent partners include: Hql3(cyclin Dl), 4pl6.3 (FGFR3 and MM.SET), and 16q23 (c-maf), which together are present in approximately 50% of MM tumors. Cyclin D3 is expressed at similar levels in 25 MM cell lines, except for one cell line that expresses nearly ten times as much cyclin D3 mRNA and protein as any other cell line. In this MM cell line, FISH analyses confirmed the presence of a t(6; 14)(p21 ;q32) translocation, with close juxtaposition of cyclin D3 and IgH Ea enhancer sequences. The cloned translocation breakpoint junction occurs within a y4 IgH switch region and includes 6p21 sequences that co-localize with cyclin D3 sequences on a BAC clone. In screening a panel of 30 MM tumors, we identified a single tumor with at(6;22)(p21;qll) translocation, with cyclin D3 and CX enhancer sequences juxtaposed on der(6). As a result the IgH and IgX translocations bracket the cyclin D3 gene, similar to results obtained for other genes (c-myc, c-maf) dysregulated by Ig translocations. From conventional cytogenetic and/or SKY analyses of several hundred MM tumors, the t(6;14)(p21;q32) translocation is present in about 2-3% of tumors. Additional FISH analyses of metaphase chromosomes confirm that: 1) cyclin D3 and IgH E<x enhancer sequences are juxtaposed in 4 M VI tumors with t(6;14)(p21;q32); and 2) in at least 3 of these tumors the BAC FISH probe described above identifies both der(14) and der(16), indicating that the breakpoints occur no more than 200 kb centromeric to cyclin D3. We hypothesize that primary [g translocations which dysregulate either cyclin Dl or cyclin D3 promote the transformation of quiescent long-lived plasma cells into proliferating MGUS tumor cells.
|Original language||English (US)|
|Issue number||11 PART I|
|State||Published - Dec 1 2000|
ASJC Scopus subject areas
- Cell Biology