Recurrent immunoglobulin gene translocations identify distinct molecular subtypes of myeloma

1569-8041

chromosomal translocations ; cyclin D1 ; FGFR3 ; MMSET ; multiple myeloma

Springer Online Journal Archives 1860-2000

Medicine

Abstract Background:Chromosome translocations involving the immunoglobulinheavy chain gene (IgH) on 14q32 are a seminal event in the pathogenesis ofmany B-cell malignancies. Since myeloma is a post-germinal center tumor ofmature, isotype switched plasma cells, we hypothesized that 14q32translocations would usually involve IgH switch regions. Materials and methods:We analyzed a panel of 21 human myelomacell lines using a Southern blot assay to detect illegitimate rearrangementsinvolving the switch regions. We then cloned the breakpoints, developed probesfor FISH analysis, and characterized the oncogenes dysregulated by thetranslocations. Results:Only half of the cell lines demonstrated a 14q32abnormality by conventional karyotypic analysis, but we were able to identifytranslocations involving IgH switch regions in 15 of 21 lines, including allof the lines in which a 14q32 translocations was notidentified byconventional karyotypic analysis. Six cell lines have an Ig translocationinvolving 11q13 with overexpression of cyclin D1. Six cell lines have an Igtranslocation involving 16q23 with overexpression of c-maf. Fivelines have an Ig translocations involving 4p16 with overexpression of FGFR3and a novel gene, MMSET. The 4p16 breakpoints occur within the 5′introns of MMSET, and are associated with IgH-MMSET hybrid mRNA transcripts.The remaining five cell lines have translocations involving other loci,including: 6p25 (MUM1), 8q24 (c-myc), and 21q22 (?AML1). Conclusions:Recurrent Ig translocations identify at least threedistinct molecular subtypes of myeloma. Our long-term goal is to determine ifthere are phenotypic, prognostic and therapeutic differences associated withthese molecular subtypes.

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