V(H) gene analysis of clonally related IgM and IgG from human lymphoplasmacytoid B-cell tumors with chronic lymphocytic leukemia features and high serum monoclonal IgG

Abstract

An unusual group of human B-cell tumors with cellular features of chronic lymphocytic leukemia or lymphoplasmacytoid leukemia, together with high levels of a monoclonal IgG serum protein, has been investigated. Analysis of tumor-derived V(H) genes of neoplastic B lymphocytes was used to determine the clonal relationship between the IgM expressed or secreted by the tumor cells and the IgG serum paraprotein. In all five cases, V(H) gene sequences showed transcripts of IgM and IgG of common clonal origin. Sequences were derived from V(H)3 (4 of 5) and V(H)1 (1 of 5) families and were all highly somatically mutated with strong evidence for antigen selection. There was no intraclonal variation detectable in either IgM or IgG sequences. In 3 of 5 cases, in which monoclonal IgM and IgG were found in serum, the V(H) genes combined to Cμ or Cγ, showed identical mutational patterns. However, in 2 of 5 cases, in which IgM was confined to cell expression with only monoclonal IgG in serum, sequences of the V(H) transcripts of IgM and IgG showed many shared mutations but also numerous differences. In these cases, the level of mutation was similar in IgM and IgG and both appeared to be antigen selected. In summary, the final neoplastic event in this group of tumors has apparently occurred at the point of isotype switch from IgM to IgG, leading to dual isotype synthesis basis. In the group that secreted both isotypes, the mutation pattern was identical, indicating either synthesis by a single cell, or silencing of mutational activity before switching. In the group that did not secrete IgM, cells of each isotype were distinct and reflected e divergent mutational history.