Promiscuous translocations into igh switch regions: The genetic hallmark of multiple myeloma

Dysregulation of oncogenes by translocation into the IgH locus at 14q32.3 is a critical event in many B cell malignancies. Based on the site of the breakpoint (JH vs. switch region), the translocations are thought to occur during either VDJ or isotype switch recombination. In multiple myeloma (MM) translocations at 14q32.3 have been reported with variable frequency (20-40%). The other partner has been identified rarely, but includes bcl-1 (25%), bcl-2 (5%), and c-myc (<5%). Hypothesizing that translocations are mediated by errors in IgH switch recombination in MM, we developed a Southern blot assay to distinguish switch recombinations as either legitimate (i.e. occurring between two switch regions) or not, postulating that an iilegitimate switch recombination site represents a potential translocation breakpoint. In 12/13 human myeloma cell lines we identified an illegitimate switch recombination site. We have cloned six of these, and they are all translocation breakpoints involving 14q32: 4pl3, 6?, two 1 Iql3, 16q24, and 21?. In two lines that over-express cyclin Dl, chromosome 11 telomeric to the bcl-1 locus is translocated into a SY region. Interestingly, a karyotypically identifiable t(l 1 ;14)(ql3;q32) is present in only one of these two cell lines. We are in the process of cloning the remainder of the breakpoints, determining the partner chromosomes involved, and the identity of the genes dysrcgulated. Thus it appears that a translocation to an IgH switch site is a common event in MM, and is consistent with the hypothesis that MM cells correspond to a long-lived plasma cell that has undergone IgH switch recombination as it passes from a germinal center to the bone marrow. Identification of the various partner chromosomes involved in 14q32 translocations and of the dysregulated oncogenes should further our understanding of the pathogenesis of myeloma.