Assessment of the role of clonogenic B lymphocytes in the pathogenesis of multiple myeloma.
The identifiable neoplastic cell in multiple myeloma is the plasma cell, which usually synthesizes and secretes a monoclonal immunoglobulin. However, there exists the possibility that the neoplastic event has occurred in a less mature clonally-related cell, such as a B lymphocyte, prior to Ig class switching. Since the presence of such a clonogenic cell could influence design of therapy, particularly with monoclonal antibodies, we have used the analysis of tumour-related VH genes to approach this question. Cloning and sequencing of PCR products from VH genes of tumour cells obtained from 4/4 patients with myeloma revealed significant mutation of the genes as compared to germ line sequences. In all cases the mutations were scattered throughout the variable region, with a pattern which did not indicate a role for antigen in selection. Importantly for therapy, multiple VH sequences from all patients were completely homogeneous, with no intraclonal variation. These findings indicate that, although IgM-positive clonogenic cells may exist, it is unlikely that they are involved in continuous maintenance of the malignant isotype-switched cell population. One possibility is that the B-cell progenitor population has to undergo further chromosomal changes to generate the malignant cell, and that this occurs at a more mature stage; in this case, antibody therapy should be aimed primarily at the more differentiated cells.
Sahota
S
S
Molecular Immunology Group, Tenovus Laboratory, Southampton University Hospitals, UK.
Hamblin
T
T
Oscier
D G
DG
Stevenson
F K
FK
D000595:Amino Acid Sequence; D001402:B-Lymphocytes / Q000276:immunology*; D001483:Base Sequence; D001853:Bone Marrow / Q000276:immunology / Q000473:pathology; D002999:Clone Cells; D003001:Cloning, Molecular; D017931:DNA Primers; D018076:DNA, Complementary; D005803:Genes, Immunoglobulin; D006801:Humans; D007070:Immunoglobulin A / Q000235:genetics; D007074:Immunoglobulin G / Q000235:genetics; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D008969:Molecular Sequence Data; D009101:Multiple Myeloma / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D009154:Mutation; D016133:Polymerase Chain Reaction; D012689:Sequence Homology, Nucleic Acid
D017931:DNA Primers; D018076:DNA, Complementary; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region