Cyclin D3 at 6p21 is dysregulated by recurrent chromosomal translocations to immunoglobulin loci in multiple myeloma

Reciprocal chromosomal translocations, which are mediated by errors in immu noglobulin heavy chain (IgH) switch recombination or somatic hypermutation as plasma cells are generated in germinal centers, are present in most mult iple myeloma (MM) tumors. These translocations dysregulate an oncogene that is repositioned in proximity to a strong IgH enhancer. There is a promiscu ous array of nonrandom chromosomal partners land oncogenes), with the 3 mos t frequent partners (11q13 [cyclin D1]; 4p16 [FGFR3 and MMSET]; 16q23 [c-ma f]) involved in nearly half of MM tumors. It is now shown that a novel t(6; 14)(p21;q32) translocation is present in 1 of 30 MM cell lines and that thi s cell line uniquely overexpresses cyclin D3, The cloned breakpoint juxtapo ses gamma 4 switch sequences with 6p21 sequences that are located about 65 kb centromeric to the cyclin D3 gene. By metaphase chromosome analysis, the t(6;14) (p21;q32) translocation was identified in 6 of 150 (4%) primary MM tumors. Overexpression of cyclin D3 messenger RNA (mRNA) was identified by microarray RNA expression analysis in 3 of 53 additional primary MM tumors , each of which was found to have a t(6;14) translocation breakpoint by int erphase fluorescence in situ hybridization analysis. One tumor has a t(6;22 )(p21;q11) translocation, so that cyclin D3 is bracketed by the IgL and IgH breakpoints. These results provide the first clear evidence for primary dy sregulation of cyclin D3 during tumorigenesis, It is suggested that the ini tial oncogenic event for most MM tumors is a primary immunoglobulin translo cation that dysregulates cyclin D1, cyclin D3, and other oncogenes to provi de a proliferative stimulus to postgerminal center plasma cells. (C) 2001 b y The American Society of Hematology.