IgH translocations in multiple myeloma

Based on our summary presentation of the information described above, we propose a working multistep model of the molecular pathogenesis of myeloma (Figure 2). The cell which gives rise to myeloma appears to have passed through the pathway that generates the long-lived plasma cell that has a phenotype similar to myeloma cells. Thus the oncogenic events in myeloma either occur after or do not interfere with the normal maturation process that generates lone-lived plasma cell. Like a long-lived plasma cell, a myeloma cell has undergone three developmentally regulated changes in the DNA structure of the IgH and IgL loci, including productive V(D)J recombination of its IgH and IgL genes, somatic hypermutation of the IgH and IgL V regions, and productive IgH switch recombination to another IgH isotype. It is attractive to speculate that errors in one or more of these processes have caused genetic changes that contribute to the malignant process. A chromosome translocation to the IgH locus, most frequently into a switch region, is a nearly universal event in myeloma cell lines, and it appears to be equally frequent in primary tumor samples. We postulate that these translocations occur at the time of isotype switch recombination, on the non-productive allele. Since MGUS and myeloma share the same legitimate switch recombination on the productive allele, they may also share the same illegitimate switch recombination on the non-productive allele. The result of these translocations is to dysregulate the expression of an oncogene by juxtaposing it to the strong regulatory sequences of the IgH locus, resulting in immortalization of the malignant clone. The presence of intraclonal heterogeneity in the Ig hypervariable regions in MGUS indicates that these cells are still subject to somatic hypermutation. Perhaps spillover of this process onto ras or a tumor suppressor gene on chromosome 13 results in the selection of a single clone for malignant expansion. Following immortalization, the malignant cell establishes a supportive environment in the bone marrow with a network of cytokines, adhesion molecules and other co-stimulatory interactions with the stromal cells. Further mutations lead to stromal cell independent growth, and escape from the bone marrow microenvironment.