<i>MYD88</i> gene and protein: molecular architecture, signalling mechanisms and clinical implications in lymphoid malignancies

MYD88 is a signal-transducing adaptor protein that plays a central role in Toll-like receptor and interleukin 1 receptor signalling through activation of the NF-κB pathway. The somatic L265P mutation in MYD88 represents a recurrent gain-of-function alteration in mature B-cell neoplasms, most notably lymphoplasmacytic lymphoma (LPL)/Waldenström macroglobulinaemia (WM) (&gt;90%), IgM monoclonal gammopathy of undetermined significance (27%–87%) and activated B-cell-type diffuse large B-cell lymphoma (DLBCL), particularly those arising in immune-privileged sites such as the central nervous system (CNS) and testis. The L265P substitution promotes constitutive myddosome assembly, IRAK1/4 recruitment and aberrant Bruton tyrosine kinase (BTK) activation, resulting in sustained NF-κB signalling independent of receptor engagement. Concurrent mutations—including CXCR4 in LPL and CD79B in DLBCL—define distinct molecular subtypes with prognostic and therapeutic implications. MYD88 mutation status serves as a valuable diagnostic biomarker, aiding differentiation of LPL from morphological mimics and enabling liquid biopsy approaches in primary CNS lymphoma. The prognostic significance of L265P is context-dependent: it confers favourable outcomes in WM but portends inferior survival in DLBCL. Therapeutically, MYD88 L265P predicts response to BTK inhibitors in WM, although concurrent CXCR4 mutations attenuate treatment efficacy. Detection methodologies include allele-specific PCR for targeted L265P detection and next-generation sequencing for comprehensive mutational profiling. This review summarises the molecular biology, disease associations, clinical utility and therapeutic implications of MYD88 mutations in lymphoid malignancies.