{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T12:16:54Z","timestamp":1788351414591,"version":"build-2803163510"},"reference-count":0,"publisher":"American Society of Hematology","license":[{"start":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T00:00:00Z","timestamp":1788307200000},"content-version":"vor","delay-in-days":1,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"abstract":"<jats:p>Genetic alterations activating NF\u2011\u03baB have been described in mature B\u2011cell malignancies. These alterations include loss of the negative regulator TRAF3, allowing NIK (NF\u2011\u03baB-inducing kinase) to drive non-canonical NF\u2011\u03baB (ncNF\u2011\u03baB) signaling. In this study, we characterized two recurrent synonymous variants of MAP3K14, the gene encoding NIK, across mature B\u2011cell malignancies including chronic lymphocytic leukemia, lymphoplasmacytic lymphoma\/Waldenstr\u00f6m's macroglobulinemia, multiple myeloma and mantle cell lymphoma. These variants were shown to introduce splice donor sites that result in removal of the critical TRAF3 binding motif. Cell line models prime edited to contain the synonymous variants demonstrated NF\u2011\u03baB activation and transcriptional reprogramming with enhanced cell proliferation and survival, as well as increased secretion of several cytokines\/chemokines including IP10\/CXCL10. We also characterized distinctive cell surface proteomic changes with NF\u2011\u03baB activation, identifying candidate markers (e.g.,CD132\/IL\u20112R\u03b3) for assessing NF\u2011\u03baB activation at a single cell level using flow cytometry. This study expands the spectrum of genetic lesions that result in activation of NF\u2011\u03baB in mature B\u2011cell malignancies and highlights our incomplete understanding of NF\u2011\u03baB drivers in mature B\u2011cell malignancies.<\/jats:p>","DOI":"10.1182\/blood.2026034228","type":"journal-article","created":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T11:32:43Z","timestamp":1788348763000},"update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":0,"title":["MAP3K14 (NIK) synonymous variants drive altered splicing to activate NF-\u03baB in mature B-cell malignancies"],"prefix":"10.1182","author":[{"given":"Eric Wenlong","family":"Li","sequence":"first","affiliation":[{"name":"Walter and Eliza Hall Institute of Medical Research, Parkville, 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Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7417-4343","authenticated-orcid":false,"given":"Ing-Soo","family":"Tiong","sequence":"additional","affiliation":[{"name":"Peter MacCallum Cancer Centre, Melbourne, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vineet","family":"Vaibhav","sequence":"additional","affiliation":[{"name":"Walter and Eliza Hall Institute of Medical Research, Parkville, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2364-6299","authenticated-orcid":false,"given":"Jumana","family":"Yousef","sequence":"additional","affiliation":[{"name":"The Walter and Eliza Hall Institute of Medical Research, Parkville, 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Siang","family":"Huang","sequence":"additional","affiliation":[{"name":"The Walter & Eliza Hall Institute of Medical Research, Parkville, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piers","family":"Blombery","sequence":"additional","affiliation":[{"name":"Peter MacCallum Cancer Centre, Melbourne, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","published-online":{"date-parts":[[2026,9,1]]},"container-title":["Blood 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