MYD88 Mutations: Transforming the Landscape of IgM Monoclonal Gammopathies

Abstract

The MYD88 gene has a physiological role in the innate immune system. Somatic mutations in MYD88, including the most common L265P, have been associated with the development of certain types of lymphoma. MYD88^L265P is present in more than 90% of patients with Waldenström's macroglobulinemia (WM) and IgM monoclonal gammopathy of undetermined significance (IgM-MGUS). The absence of MYD88 mutations in WM patients has been associated with a higher risk of transformation into aggressive lymphoma, resistance to certain therapies (BTK inhibitors), and shorter overall survival. The MyD88 signaling pathway has also been used as a target for specific therapies. In this review, we summarize the clinical applications of MYD88 testing in the diagnosis, prognosis, follow-up, and treatment of patients. Although MYD88^L265P is not specific to WM, few tumors present a single causative mutation in a recurrent position. The role of the oncogene in the pathogenesis of WM is still unclear, especially considering that the mutation can be found in normal B cells of patients, as recently reported. This may have important implications for early lymphoma detection in healthy elderly individuals and for the treatment response assessment based on a MYD88^L265P analysis.

Keywords: Waldenström’s macroglobulinemia; hematologic neoplasms; signal transduction; targeted therapy.

Figure 1

Schematic representation of the MYD88 gene structure and the L265P mutation at the DNA and protein levels.

Figure 2

Representation of the MyD88 and related pathways that can be targeted by specific drugs. Components of the pathways activated by MYD88^L265P mutation, such as BTK, IRAKs, and HCK, have proven to be relevant targets for lymphomas. MyD88 is also being used for T-cell immunotherapy as part of CAR T cells, synthetic coreceptors (CD8α:MyD88), or peptides that can induce T-cell responses.