Identification of Three Novel Chromosomal Translocation Partners Involving the Immunoglobulin Loci in Newly Diagnosed Myeloma and Human Myeloma Cell Lines.

Abstract

Abstract Chromosomal translocations involving the immunoglobulin heavy-chain (IgH) locus at 14q32 are genetic hallmarks of human multiple myeloma (MM) and are likely primary oncogenic events in myeloma transformation. Common recurrent translocation partner genes of IgH account for 40–50% of cases and these rearrangements result in the transcriptional dysregulation of various proto-oncogenes such as CCND1, CCND3, FGFR3/MMSET, c-MAF, MAFB, MUM 1(IRF-4), c-MYC and it is becoming clear that these dysregulated genes play important roles in the pathogenesis and the treatment outcome of MM. Although the frequency of other partner genes of IgH translocations may be rare (<1%), it is possible that many genes not currently identified as translocation partners are functionally converged into several signal pathways and play important roles as well. Through global gene expression profiling (GEP) studies of a large population of newly diagnosed MM, we have recently reported that dysregulation of any one of the three D-type cyclins is seen in almost all newly diagnosed MM and most patients with high levels of CCND2 expression was highly correlated with expression of c-MAF, MAFB or FGFR3/MMSET. In order to identify novel translocation partner genes in MM we combined GEP and fluorescence in situ hybridization (FISH) analysis in a large population of newly diagnsoed myeloma. We investigated whether IGH-CCND2 and IGH-MAFA translocations are seen in patients exhibiting high levels of CCND2 expression but not expressing c-MAF, MAFB, or FGFR3/MMSET. We also looked for a breakpoint and targeted gene at a non-random breakpoint at the 11q23 locus in 20 MM patients with 11q23 abnormalities detected by conventional G-banding. Here we report evidence of an IGH-CCND2 fusion in a newly diagnosed case of MM and an IGH-MAFA fusion in a newly diagnosed MM and an MGUS and also mapped the 11q23 breakpoint to within 100 kb in a newly diagnosed MM and a human myeloma cell line, NCU-MM-1 and identified an IGL Pou2AF1 fusion in the NCU-MM-1 line. Importantly these translcoatios do not involve the MLL or ATM genes. These three genes were all highly expressed as detected by GEP or quantitive RT-PCR in the samples in which these genes were translocated to IG loci. Although the frequency of these 3 translocations are very rare, they further the concept of a critical role of CCND2 expression in myelomegenesis and identifed the transcriptional coactivator Pou2AF1, which specifically associates with either OCT1 or OCT2, in the B-cell response to antigens and required for the formation of germinal centers, as a potential new translocation target in myeloma. Finally, our strategy of combining GEP signatures and cytogenetic analyses appears to be a practical means of identifying new IG- mediated translocations in myeloma.