Professor Steven Treon outlines the impact of the MYD88L^!S4/ mutation on the toll-like receptor (TLR) signalling pathway. Prof Treon describes the downstream consequences of the MYD88^*NUM} mutation including that it leads to NFĸB signalling which has implications for growth and survival of malignant B-cells. He also explains pHCK promotes pro-survival signalling in MYD88-mutated B-cells. He explains how Bruton’s tyrosine kinase (BTK) inhibitors can be used to target the pathway in B-cell lymphomas like Waldenström’s macroglobulinemia.