Multiple myeloma is a plasma cell tumor with frequent Ig translocations

Germinal center B cells uniquely modify the DNA of Ig genes through sequential rounds of somatic hypermutation and antigen selection, and also by IgH switch recombination. Post-germinal center B cells can generate plasmablasts that have successfully completed somatic hypermutation and IgH switching before migrating to the bone marrow, where stromal cells enable terminal differentiation into long-lived plasma cells. MGUS and MM are characterized by the accumulation of transformed plasmablasts/plasma cells at multiple sites in the bone marrow. Importantly, although MM is more prolif-erative than MGUS, both tumors have an extremely low rate of proliferation. The combination of karyotypic complexity, inability to efficiently perform conventional cytogenetics on low proliferative tumors, and the telomeric location of some translocation partners delayed the identification of Ig translocations in MGUS and MM. An important initial step in solving this problem was the identification and cloning of IgH switch-region translocation breakpoints in HMCL. Interphase fluorescence in situ hybridization (FISH) using probes flanking the cloned breakpoints identifies karyotypic abnormalities even in non-dividing cells and has enabled the analysis of primary MGUS and MM tumors. Several studies have shown that most MM tumors have an IgH translocation that non-randomly involves one of many potential chromosomal partners. The prevalence of IgH translocations varies with the stage of disease: 46-48% in MGUS or smoldering MM, 55-73% in intramedullary MM, 85% in primary plasma cell leukemia, and >90% in HMCL.

The karyotypes of MM are more similar to those of epithelial tumors and the blast phase of chronic myelogenous leukemia than are other hematopoietic tumors. However, the ratio of balanced translocations versus unbalanced translocations is substantially higher in MM than in epithelial tumors. Numer ical chromosomal abnormalities are present in virtually all MM tumors and most, if not all, MGUS tumors. There is non-random involvement of different chromosomes in different myeloma tumors, and often heterogeneity among cells within a tumor. Comparative genomic hybridization (CGH) studies show that unbalanced chromosome structural changes are present in all plasma cell leukemias and most, if not all, MM tumors. Chromosomal gains that recur in more than 30% of MM tumors include 1q, 3q, 9q, 11q and 15q, the consequences of which remain to be determined, and the most frequent chromosome loss is 13q (see below). As CGH does not detect balanced translocations, a more comprehensive view is provided by spectral karyotype (SKY) analyses, although these are complicated by the fact that metaphase spreads can be obtained in only about 20% of cases. It is thought that karyotypic complexity increases during tumor progression, although karyotypic progression has not been well documented. Understanding how the karyotype correlates with disease severity is important because the detection of an abnormal karyotype correlates with an increase in the plasma cell labeling index and poor prognosis, and hypodiploidy is associated with a poorer prognosis than hyperdiploidy.

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