{"entity":{"id":"myd88-l265p","kind":"term","name":"MYD88 L265P and CXCR4 mutations","aka":["MYD88","MYD88 L265P","MYD88 mutation","MYD88-mutated","MYD88 wild-type","MYD88wt","CXCR4 mutation","CXCR4 S338X","CXCR4 WHIM-like mutation","MYD88/CXCR4 genotype","CD79B mutation","MCD subtype DLBCL","cluster 5 DLBCL"],"tldr":"One letter change in MYD88 (L265P) keeps a B-cell survival signal permanently on; it is found in more than nine in ten Waldenström's macroglobulinaemia, most primary CNS and testicular lymphomas and a poor-risk group of DLBCL, and it predicts that BTK inhibitors will work, while a second mutation in CXCR4 predicts that they will work more slowly.","summary":"What is measured: the MYD88 L265P point mutation and, alongside it, CXCR4 nonsense or frameshift mutations (S338X the commonest) and CD79B mutations. How: allele-specific PCR or next-generation sequencing on bone marrow in Waldenström's, on tumour tissue in lymphoma, and on cerebrospinal fluid or vitreous cell-free DNA in CNS and ocular lymphoma, where it helps make a diagnosis without a brain biopsy. Frequencies: Waldenström's 90 to 95 percent, IgM MGUS 50 to 80 percent, marginal zone lymphoma under 10 percent (so a wild-type result favours marginal zone over Waldenström's), primary CNS lymphoma 60 to 80 percent with CD79B, and the MCD or cluster 5 subgroup of activated B-cell DLBCL; CXCR4 mutations are subclonal and present in 30 to 40 percent of Waldenström's. What a result changes: in Waldenström's, MYD88-mutated disease responds best to ibrutinib, zanubrutinib and acalabrutinib (ASPEN compared zanubrutinib and ibrutinib), CXCR4-mutated disease responds more slowly and less deeply with more IgM flare, favouring zanubrutinib or bendamustine-rituximab and proteasome-inhibitor regimens, and MYD88 wild-type disease does poorly on BTK inhibitors, steering to chemo-immunotherapy; in CNS lymphoma it supports BTK inhibitor trials, and in MCD DLBCL ibrutinib added to R-CHOP helped younger patients in a PHOENIX subgroup. Where it matters: Waldenström's, primary CNS lymphoma, marginal zone lymphoma and DLBCL.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/MYD88","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/MYD88"},{"label":"Ngo et al., Nature 2011: oncogenically active MYD88 mutations in human lymphoma","url":"https://doi.org/10.1038/nature09671"},{"label":"Treon et al., N Engl J Med 2012: MYD88 L265P somatic mutation in Waldenstrom macroglobulinaemia","url":"https://doi.org/10.1056/NEJMoa1200710"},{"label":"Schmitz et al., N Engl J Med 2018: genetics and pathogenesis of diffuse large B-cell lymphoma (574 biopsies; MCD, BN2, N1, EZB)","url":"https://doi.org/10.1056/NEJMoa1801445"}],"tags":[],"related":["cxcr4","btk","ibrutinib","zanubrutinib","acalabrutinib","bendamustine","cell-of-origin","ngs","ctdna"],"cancers":["waldenstrom","primary-cns-lymphoma","marginal-zone-lymphoma","dlbcl","malt-lymphoma","non-hodgkin-lymphoma"],"sections":[],"technologies":[],"targets":["myd88","btk","cd79b"],"drugs":[],"companies":[],"institutions":[],"pathways":["inflammation-nfkb","bcr-signalling"],"terms":["lymphoma-bio-lymphgen"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":["The mechanism, and the primary figures. MYD88 is the adaptor of the toll-like and interleukin-1 receptors, and L265P sits at an evolutionarily invariant residue in the hydrophobic core of its TIR domain. The mutant assembles a signalling complex with IRAK1 and IRAK4 without any receptor signal, driving NF-kB and JAK kinase activity; activated B-cell-like lymphoma cells carrying it die when MYD88, IRAK1 or IRAK4 are knocked down, and the wild-type protein cannot rescue them, which is what makes it a gain-of-function driver rather than a passenger. The original series found it in 29% of activated B-cell-like diffuse large B-cell lymphomas, rarely or not at all in other subtypes and in Burkitt lymphoma, and in 9% of MALT lymphomas (Ngo 2011). In Waldenstrom macroglobulinaemia, whole-genome sequencing found it in all 10 patients with paired normal tissue, and Sanger sequencing in 49 of 54 patients and in 91% of all lymphoplasmacytic lymphoma including the non-IgM form, absent from paired normal tissue and from healthy donor B cells (Treon 2012). With CD79B mutation it defines the MCD genetic subtype of large B-cell lymphoma (Schmitz 2018)."],"category":"Biomarkers"},"route":"/terms/myd88-l265p/","neighbours":{"target":[{"id":"btk","kind":"target","name":"BTK (Bruton tyrosine kinase)","route":"/targets/btk/"},{"id":"cd79b","kind":"target","name":"CD79b","route":"/targets/cd79b/"},{"id":"cxcr4","kind":"target","name":"CXCR4","route":"/targets/cxcr4/"},{"id":"myd88","kind":"target","name":"MYD88","route":"/targets/myd88/"}],"drug":[{"id":"acalabrutinib","kind":"drug","name":"Acalabrutinib","route":"/drugs/acalabrutinib/"},{"id":"bendamustine","kind":"drug","name":"Bendamustine","route":"/drugs/bendamustine/"},{"id":"ibrutinib","kind":"drug","name":"Ibrutinib","route":"/drugs/ibrutinib/"},{"id":"zanubrutinib","kind":"drug","name":"Zanubrutinib","route":"/drugs/zanubrutinib/"}],"term":[{"id":"cell-of-origin","kind":"term","name":"Cell of origin (GCB vs ABC)","route":"/terms/cell-of-origin/"},{"id":"ctdna","kind":"term","name":"Circulating tumour DNA (ctDNA)","route":"/terms/ctdna/"},{"id":"lymphoma-bio-lymphgen","kind":"term","name":"LymphGen and the genetic clusters of large B-cell lymphoma","route":"/terms/lymphoma-bio-lymphgen/"},{"id":"ngs","kind":"term","name":"Next-generation sequencing (NGS)","route":"/terms/ngs/"}],"cancer":[{"id":"dlbcl","kind":"cancer","name":"Diffuse large B-cell lymphoma","route":"/cancers/dlbcl/"},{"id":"malt-lymphoma","kind":"cancer","name":"Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma)","route":"/cancers/malt-lymphoma/"},{"id":"intravascular-large-b-cell-lymphoma","kind":"cancer","name":"Intravascular large B-cell lymphoma","route":"/cancers/intravascular-large-b-cell-lymphoma/"},{"id":"marginal-zone-lymphoma","kind":"cancer","name":"Marginal zone lymphoma","route":"/cancers/marginal-zone-lymphoma/"},{"id":"non-hodgkin-lymphoma","kind":"cancer","name":"Non-Hodgkin lymphoma (all types)","route":"/cancers/non-hodgkin-lymphoma/"},{"id":"primary-cns-lymphoma","kind":"cancer","name":"Primary CNS lymphoma","route":"/cancers/primary-cns-lymphoma/"},{"id":"primary-testicular-lymphoma","kind":"cancer","name":"Primary large B-cell lymphoma of the testis","route":"/cancers/primary-testicular-lymphoma/"},{"id":"waldenstrom","kind":"cancer","name":"Waldenström macroglobulinaemia","route":"/cancers/waldenstrom/"}],"pathway":[{"id":"bcr-signalling","kind":"pathway","name":"B-cell receptor / BTK signalling (to NF-κB)","route":"/pathways/bcr-signalling/"},{"id":"inflammation-nfkb","kind":"pathway","name":"Inflammation & NF-κB","route":"/pathways/inflammation-nfkb/"}],"biomarker":[{"id":"cd79b-itam-mutation","kind":"biomarker","name":"CD79B ITAM mutation","route":"/biomarkers/cd79b-itam-mutation/"}]}}