Myeloma phenotype: clues to disease origin and manifestation.

Phenotypic analysis of myeloma cells has had a major impact on our understanding of the development of the disease. Heterogeneity in the expression of lineage- and differentiation-associated antigens has helped delineate a circulating clonal premyeloma cell compartment coexpressing CD19 and CD11b. These cells can be stimulated in vitro to proliferate and differentiate into the mature myeloma cells. Other studies have demonstrated the involvement of very early bone marrow B lymphocytes, which could be differentiated into myeloma cells through a CD10-positive intermediate stage. These data suggest that myeloma originates in the bone marrow and is mobilized through the circulation to and from extramedullary sites, probably lymph nodes, which are required for their development. Subsequently, these cells return to the bone marrow or soft-tissue sites, using adhesion molecules for homing to sites that can provide the stimuli for expansion and maturation. Development of myeloma and disease manifestation are governed by a network of cytokines. Among the cytokines, IL-6 has been promoted as the major myeloma growth factor. Recent findings indicate that, whereas myeloma cells have the ability to express both the IL-6 and its receptor gene, their ability to respond to the cytokine is minimal. The requirement in vitro for both IL-3 and IL-6 for the stimulation of premyeloma cell proliferation and differentiation suggests a role for IL-6 in affecting differentiation of myeloma progenitors and the involvement of an earlier hematopoietic progenitor. Frequent association with myeloid dysplasia and neoplasia and expression of multiple hematopoietic lineage-associated markers forward the hypothesis that myeloma originates in a hematopoietic stem cell.