MYD88 Wild Type in IgM Monoclonal Gammopathies: From Molecular Mechanisms to Clinical Challenges

High frequencies of MYD88L265P mutation are observed in IgM monoclonal gammopathies, and specifically in Waldenström macroglobulinemia (WM), indicating this mutation as a potential disease biomarker. Given the fact that MYD88L265P mutation has been described as a key driver mutation, has increased our understanding of the biology behind MYD88 signaling and helped us to identify the functional components which could be targeted. On the other hand, the absence of the MYD88L265P mutation in patients with IgM monoclonal gammopathies has been associated with a higher risk of transformation to aggressive lymphomas, resistance to several therapies, and shorter overall survival. The present review focuses on the molecular mechanisms that shape the signaling pattern in MYD88WT cells, as well as on the clinical implications and therapeutic challenges of WM patients that harbor the MYD88WT genotype.