MYD88^L265P harbors a leucine-to-proline exchange in the hydrophobic core of its Toll/interleukin-1 receptor (TIR) domain (small red square), thus facilitating homotypic interaction with the TIR domain (small black square) of receptors from the TIR superfamily (TIRs). Upon recruitment of MYD88 to TIRs, MYD88 recruits interleukin 1 receptor-associated kinase 4 (IRAK4), which phosphorylates IRAK1 and -2 and promotes recruitment of tumor necrosis factor receptor-associated factor 6 (TRAF6). This results in ubiquitylation and activation of nuclear receptor subfamily 2 group C member 2, better known as TGF-β-activated kinase 1 (TAK1) and, ultimately, in activation of canonical NF-κB signaling. Subsequent to the discovery of the MYD88^L265P allele in ABC-DLBCL (an accomplishment of the Staudt Laboratory at the US National Cancer Institute⁴ ), the same mutation was demonstrated by investigators in Waldenström macroglobulinemia (WM),⁵  including its precursor condition immunoglobulin M (IgM) monoclonal gammopathy of undetermined significance and the related disease, IgM-associated light chain amyloidosis,⁶  in primary central nervous system lymphoma (PCNSL), in splenic marginal zone lymphoma (SMZL), in mucosa-associated lymphoid tissue (MALT) lymphoma and, rarely, in chronic lymphocytic leukemia (CLL). The mouse model of MYD88^L265P-dependent lymphoma developed by Knittel et al may be useful for studies of all of these neoplasms, and particularly WM, in which the L265P substitution occurs with the highest frequency (ie, in nearly all patients).