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 represents a recurrent gain-of-function alteration in mature B-cell neoplasms, most notably lymphoplasmacytic lymphoma (LPL)/Waldenström macroglobulinaemia (WM) (>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 in LPL and in DLBCL-define distinct molecular subtypes with prognostic and therapeutic implications. 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, L265P predicts response to BTK inhibitors in WM, although concurrent 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 mutations in lymphoid malignancies.