Somatic mutations in MYD88 are found in 90% of patients with Waldenström's macroglobulinemia.

  • Major finding: Somatic mutations in MYD88 are found in 90% of patients with Waldenström's macroglobulinemia.

  • Clinical relevance: Inhibition of MYD88 signaling decreased NF-κB activity in MYD88-mutant cells.

  • Impact: MYD88 L265P may be important for diagnosis and treatment of Waldenström's macroglobulinemia.

Waldenström's macroglobulinemia is a rare, incurable, immunoglobulin M–secreting lymphoplasmacytic lymphoma for which the underlying oncogenic events are unknown, although familial clustering of some cases of Waldenström's macroglobulinemia suggests a genetic basis for this disease. Treon and colleagues performed whole-genome sequencing and confirmatory Sanger sequencing on 30 cases of Waldenström's macroglobulinemia and identified a single-nucleotide variant in myeloid differentiation primary response gene 88 (MYD88) in 90% of the patients. Heterozygous MYD88 mutations were found in the majority of cases, although 4 patients had homozygous MYD88 L265P expression. This mutation, predicted to cause a leucine-to-proline change at amino acid 265 (L265P), was found in 100% of patients with a family history of Waldenström's macroglobulinemia and in 86% of patients with sporadic cases. MYD88 mutations were not identified in normal tissue samples and were rarely observed in other B-cell disorders, indicating that MYD88 L265P expression may have diagnostic utility for Waldenström's macroglobulinemia. MYD88 encodes an adaptor molecule that activates NF-κB signaling, which has been shown to contribute to the growth and survival of Waldenström's macroglobulinemia cells. Consistent with the possibility that MYD88 L265P induces aberrant NF-κB pathway activation, high nuclear levels of NF-κB p65 were observed in MYD88-mutant Waldenström's macroglobulinemia cells. In vitro treatment with a peptide that inhibits MYD88 homodimerization or an inhibitor of interleukin-1 receptor–associated kinase (IRAK), a MYD88 binding partner, led to a marked decrease in nuclear levels of NF-κB p65, suggesting that direct targeting of MYD88–IRAK signaling may be an effective therapeutic approach for Waldenström's macroglobulinemia.

Treon SP, Xu L, Yang G, Zhou Y, Liu X, Cao Y, et al. MYD88 L265P somatic mutation in Waldenström's macroglobulinemia. N Engl J Med 2012;367:826–33.

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