Multiple Myeloma: New Evidence and Insights from the Immunoglobulin Heavy Chain Gene and Phenotypes

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Abstract
DNA analysis of the Ig genes has been utilized to delineate the stages of differentiation of normal and malignant B-lineage cells, since the mechanisms involved in V(D)J recombination, somatic hypermutations, and class switch are developmentally regulated. Somatic mutations which result in amino acid substitutions are observed frequently in the Ig variable region genes in multiple myeloma (MM), but there is no intraclonal variation. This fact suggests that the target cell of malignant transformation in MM is a B-lineage cell which already has undergone antigenic selection. This B-lineage cell probably corresponds to a pre-plasma cell or a plasma cell rather than a memory B cell. Tumour cells which share an identical third-complementarity-determining-region (CDR3) sequence with the myeloma cells can be detected from the various fractions representing different stages of B-cell differentiation, such as CD34+, CD20+CD10+, CD20+CD21+, CD20+CD19- cells from the peripheral blood. Thus, the tumour cells in MM are composed of immunophenotypically heterogeneous subpopulations at various stages of differentiation, similar to normal B-lineage cells. These results imply that there is an analogous developmental pathway between the normal B-lineage cells and the tumour cells of MM. Dedifferentiation to the stem cell level may be essential to the malignant transformation in MM.