Genetics and cytogenetics of Waldenstrom's macroglobulinemia

Waldenstrom's macroglobulinemia (WM) is a clonal B-cell disorder characterized by the production of a monoclonal paraprotein and lymphoplasmacytic clonal expansion. The genetic basis of this disorder is poorly understood. We have recently found that the genetic makeup of WM cells is different from that commonly reported for multiple myeloma (MM), follicular lymphoma, and B-cell chronic lymphocytic leukemia. Translocations involving the immunoglobulin heavy chain locus (IgH) translocations could not be detected in any case, and a molecular analysis showed that the IgH locus switch mu retained its germline configuration. Aneuploidy was not detected using chromosome enumeration probes. The only recurrent chromosome abnormality found was deletion of 6q21. The lack of legitimate of illegitimate rearrangements at the IgH locus suggests that other mechanisms are involved in the pathogenesis of the disorder. Given the clear evidence of a familial form of WM and the currently presumed genomic stability of the clonal cells, it is likely that a single gene defect may be responsible for disease pathogenesis. Having found deletions of the long arm of chromosome 6 as the only recurrent aberration, we speculate that a gene involved in B-cell maturation or survival at this locus may be inactivated as a cause of WM.