THE CLONOGENIC PRECURSOR CELL IN MULTIPLE-MYELOMA

Multiple myeloma is characterized by the monoclonal expansion of plasm a cells in the bone marrow. Although the predominant cell type is the plasma cell, the initial oncogenic transformation is considered to tak e place in a more immature B cell. There is still much controversy abo ut this precursor cell type. Phenotypic analysis of bone marrow and pe ripheral blood revealed that in multiple myeloma a great diversity exi sts in the phenotype of the cells considered to be involved. Because o f the tack of a myeloma specific genetic lesion it is very difficult t o trace back the cell in which the transforming event, leading to mult iple myeloma, took place. The only real clonal marker is the idiotype of the immunoglobulin molecule expressed by the myeloma cells. With re combinant DNA technology it is now possible to produce clonal markers for each individual myeloma patient which recognize only the immunoglo bulin genes expressed by the myeloma cell and its precursors. The sequ ences of these myeloma immunoglobulin genes do reveal a lot of informa tion about the stage in the B-cell differentiation pathway in which th e oncogenic event might have taken place. The presence of somatic muta tions in a non-random fashion without intraclonal variation leads to t he conclusion that the precursor myeloma cell could not possibly be a pre-B cell or stem cell but has to be a mature B cell that has been in contact with antigen and has past through the phase of somatic mutati on, like a memory B cell or plasmablast. The identification of a small population of clonally related pre-switched B cells in the peripheral blood, harbouring exactly the same somatic mutations as the myeloma i mmunoglobulin sequence, is not contradictory with this model although the self-renewal capacity of this population is not yet clear.