EVIDENCE FOR A BONE-MARROW B-CELL TRANSCRIBING MALIGNANT PLASMA-CELL VDJ JOINED TO C-MU SEQUENCE IN IMMUNOGLOBULIN (IGG)-SECRETING AND IGA-SECRETING MULTIPLE MYELOMAS

Multiple myeloma is a B cell malignancy characterized by the expansion of plasma cells producing monoclonal immunoglobulins (Ig). It has bee n regarded as a tumor arising at the B, pre-B lymphocyte, or even stem cell level. Precursor cells are presumed to proliferate and different iate giving rise to the plasma cell clonal expansion. Antigenic featur es and specific Ig gene rearrangement shared by B lymphocytes and myel oma cells have supported this hypothesis. However, the existence of su ch a precursor is based upon indirect evidence and is still an open qu estion. During differentiation, B cells rearrange variable (V) regions of Ig heavy chain genes, providing a specific marker of clonality. Us ing an anchor polymerase chain reaction assay, these rearranged region s from five patients with multiple myeloma were cloned and sequenced. The switch of the Ig constant (C) region was used to define the B cell differentiation stage: V regions are linked to Cmu genes in pre-B and B lymphocytes (pre-switch B cells), but to Cgamma or Calpha in post-s witch B lymphocytes and plasma cells (post-switch B cells). Analysis o f bone marrow cells at diagnosis revealed the presence of pre-switch B cells bearing plasma cell V regions still joined to the Cmu gene. The se cells were not identified in peripheral blood, where tumor post-swi tch B cells were detected. These pre-switch B cells may be regarded as potential myeloma cell precursors.