{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T10:08:13Z","timestamp":1779098893420,"version":"3.51.4"},"reference-count":50,"publisher":"BMJ","issue":"6","content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Clin Pathol"],"accepted":{"date-parts":[[2026,3,21]]},"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:p>\n                    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-\u03baB pathway. The somatic L265P mutation in\n                    <jats:italic>MYD88<\/jats:italic>\n                    represents a recurrent gain-of-function alteration in mature B-cell neoplasms, most notably lymphoplasmacytic lymphoma (LPL)\/Waldenstr\u00f6m macroglobulinaemia (WM) (&gt;90%), IgM monoclonal gammopathy of undetermined significance (27%\u201387%) 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-\u03baB signalling independent of receptor engagement. Concurrent mutations\u2014including\n                    <jats:italic>CXCR4<\/jats:italic>\n                    in LPL and\n                    <jats:italic>CD79B<\/jats:italic>\n                    in DLBCL\u2014define distinct molecular subtypes with prognostic and therapeutic implications.\n                    <jats:italic>MYD88<\/jats:italic>\n                    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,\n                    <jats:italic>MYD88<\/jats:italic>\n                    L265P predicts response to BTK inhibitors in WM, although concurrent\n                    <jats:italic>CXCR4<\/jats:italic>\n                    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\n                    <jats:italic>MYD88<\/jats:italic>\n                    mutations in lymphoid malignancies.\n                  <\/jats:p>","DOI":"10.1136\/jcp-2026-210690","type":"journal-article","created":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T17:20:44Z","timestamp":1775064044000},"page":"363-369","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["<i>MYD88<\/i>\n                    gene and protein: molecular architecture, signalling mechanisms and clinical implications in lymphoid malignancies"],"prefix":"10.1136","volume":"79","author":[{"given":"Sukanya","family":"Banerjee Nair","sequence":"first","affiliation":[{"name":"Pathology Program, Fred Hutchison Cancer Center, Seattle, Washington, USA"},{"name":"Department of Pathology, Hospital Tengku Ampuan Rahimah Klang, Klang, Malaysia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Teresa S","family":"Hyun","sequence":"additional","affiliation":[{"name":"Pathology Program, Fred Hutchison Cancer Center, Seattle, Washington, USA"},{"name":"Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3807-3638","authenticated-orcid":false,"given":"Kikkeri N","family":"Naresh","sequence":"additional","affiliation":[{"name":"Pathology Program, Fred Hutchison Cancer Center, Seattle, Washington, USA"},{"name":"Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"239","published-online":{"date-parts":[[2026,4,1]]},"reference":[{"key":"2026051802151036000_79.6.363.1","first-page":"1095","article-title":"Nucleotide sequence and expression of a cDNA encoding MyD88, a novel myeloid differentiation primary response gene induced by IL6","volume":"5","author":"Lord","year":"1990","journal-title":"Oncogene"},{"key":"2026051802151036000_79.6.363.2","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1038\/nature09671","article-title":"Oncogenically active MYD88 mutations in human lymphoma","volume":"470","author":"Ngo","year":"2011","journal-title":"Nature New Biol"},{"key":"2026051802151036000_79.6.363.3","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1200710"},{"key":"2026051802151036000_79.6.363.4","doi-asserted-by":"crossref","unstructured":"Rodriguez S , Celay J , Goicoechea I , et al . Preneoplastic somatic mutations including MYD88(L265P) in lymphoplasmacytic lymphoma. Sci Adv 2022;8.","DOI":"10.1126\/sciadv.abl4644"},{"key":"2026051802151036000_79.6.363.5","doi-asserted-by":"crossref","unstructured":"Pustelny K , Kuska K , Gorecki A , et al . Mechanism of MyD88S mediated signal termination. Cell Commun Signal 2022;20. doi:10.1186\/s12964-021-00811-1","DOI":"10.1186\/s12964-021-00811-1"},{"key":"2026051802151036000_79.6.363.6","doi-asserted-by":"crossref","unstructured":"Lee FFY , Harris C , Alper S . RNA Binding Proteins that Mediate LPS-induced Alternative Splicing of the MyD88 Innate Immune Regulator. J Mol Biol 2024;436. doi:10.1016\/j.jmb.2024.168497","DOI":"10.1016\/j.jmb.2024.168497"},{"key":"2026051802151036000_79.6.363.7","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-18-0215"},{"key":"2026051802151036000_79.6.363.8","doi-asserted-by":"crossref","unstructured":"Dossang ACG , Motshwene PG , Yang Y , et al . 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