Clonal evolution in Waldenstrom macroglobulinemia highlights functional role of B-cell receptor

Abstract

The course of clonal evolution of 2 related clones in the blood of a patient with Waldenstrom macroglobulinemia (WM) indicates the functional importance for the expression of the B-cell receptor for the survival of these malignant cells. Protein and nucleotide sequencing of the paraproteins' variable regions revealed 2 predominant V and 2 VH sequences, each set comprised in the ratio 1:1.5. The 2 VH sequences and 2 V sequences shared the same VDJ and VJ junctional sequences, respectively, indicating that 2 malignant clones had evolved from a common ancestor. This is the first report on intraclonal heterogeneity in WM. Comparison of the V and VH sequences with the closest matching known germline genes showed that they contained approximately 10 somatic mutations each. The distribution and type of mutations demonstrate that mutations have continued to accumulate in the malignant clones and that selection has been operating to preserve immunoglobulin structure. (Blood. 2001;97:321-323)

Molecular characterization of heavy chain immunoglobulin gene rearrangements in Waldenstrom's macroglobulinemia and IgM monoclonal gammopathy of undetermined significance

“…Nevertheless, five out of the 52 WM cases tested (9.6%) showed a naïve B-cell origin, which concurs with other published data. [10][11][12]24,30 This would indicate that the transformation event that leads to WM or IgM-MGUS does not necessarily target somatically mutated B cells.…”

Clonotypic IgM V/D/J sequence analysis in Waldenstrom macroglobulinemia suggests an unusual B-cell origin and an expansion of polyclonal B cells in peripheral blood

“…3 WM B cells appear to express somatically mutated IgM. [4][5][6] In a single case, Ciric et al 7 report the development of biclonal IgM in WM tumor cells. The pattern of mutations within the 2 dominant clones was suggestive of prolonged antigen selection after the malignant WM transformation event.…”

Molecular Characterization of Waldenstrom's Macroglobulinemia Reveals Frequent Occurrence of Two B-Cell Clones Having Distinct IgH VDJ Sequences

“…In these reports, however, the origins and genealogic relationships of the two coexisting clones were not addressed. In a more recent study, two clonally related IgM-producing clones were found in a WM patient, postulated to result from clonal diversification occurring after the original transformation event (23).…”