Marked karyotypic instability

locations occur as progression events. Most translocations involving the five recurrent translocation partners described above appear to be primary translocations that occurred as a result of errors in IgH switch recombination during B-cell development in germinal centers. In contrast, translocations of c-myc appear to be very late secondary events that do not involve B-cell specific recombination mechanisms, are often complex, and sometimes do not involve Ig loci. By FISH analysis, rearrangements of c-myc are reported in only 15% of MM tumors (with frequent heterogeneity within a tumor), but in nearly 40% of advanced MM tumors and 90% of HMCL. Regarding the approximately 20% of IgH translocations not involving the six recurrent partners above, little is known about the multitude of partners and oncogenes, the mechanisms that mediate these translocations, and the time(s) at which these translocations occur.

blasts, for which 30% or more of the cells can be in S phase. It is surprising, therefore, that an analysis by Bergsagel and Kuehl of combined gene expression profiling data published from two laboratories shows that the expression level of cyclin D1, cyclin D2 or cyclin D3 mRNA in MM and MGUS is distinctly higher than in normal plasma cells—comparable to the levels of cyclin D2 mRNA expressed in normal proliferating plas-mablasts (Figure 11.1). Normal hematopoietic cells, including normal B lymphocytes, plasma cells and plasmablasts, express cyclin D2 and/or D3, but little or no cyclin D1. Given the lack of cyclin D1 expression in normal lymphocytes, the occurrence of Ig translocations that dysregulate cyclin D1 or cyclin D3 in about 20% of MM tumors, the expression of cyclin D1 in nearly 40% of tumors lacking a t(11;14) translocation, and the increased expression levels of cyclin D2 in most remaining tumors, it seems apparent that almost all MM tumors dysregulate at least one of the cyclin D genes.

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