What causes Waldenström macroglobulinemia?

Updated: Feb 01, 2021
  • Author: Karen Seiter, MD; Chief Editor: Emmanuel C Besa, MD  more...
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No definite etiology exists for Waldenström macroglobulinemia. Environmental, familial, genetic, and viral factors have been reported. IgM monoclonal gammopathies of undetermined significance (MGUS) are considered a precursor of Waldenström macroglobulinemia.

A possible role for genetic factors has been suggested by reports of familial clustering of Waldenström macroglobulinemia. In one study, approximately 20% of 181 serial Waldenström macroglobulinemia patients presenting to a tertiary referral had a first-degree relative with either Waldenström macroglobulinemia or another B-cell lymphoproliferative disease. Reports of familial cases suggest a genetic predisposition. [10, 11]

The MYD88 L265P somatic mutation, in which leucine is replaced by proline at position 265, is found in white blood cells in approximately 90% of Waldenström macroglobulinemia cases. The mutation results in overactivity of the altered MyD88 protein, stimulating the signaling molecules that activate nuclear factor-kappa-B; this may protect lymphoplasmacytic cells against apoptosis. [12]

Less common somatic genetic changes that have been found in Waldenström macroglobulinemia include variants in ARID1A, which have been associated with increased disease burden, and variants in MLL2. [10]  Other MYD88 mutations have also been found. Somatic activating mutations in the C-terminal domain of the C-X-C chemokine receptor type 4 (CXCR4) gene have been found in 20% to 40% of patients. [13]

Hepatitis C, hepatitis G, and human herpesvirus 8 have been implicated, but as yet, no strong data support a causative link between these viruses and Waldenström macroglobulinemia.

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