Authors
Eric Wenlong Li, Luuk Heitink, Esther Bandala-Sanchez, Rhiannon Morris, Mark F van Delft, Angela Georgiou, Thomas E Lew, Miles B Horton, Reema Jain, Simon Monard, Natasha Silke, Kah Lok Chan, Ing-Soo Tiong, Vineet Vaibhav, Jumana Yousef, Wencke Walter, Laura F Dagley, John Silke, Andrew H Wei, Torsten Haferlach, Andrew W Roberts, David Ching Siang Huang, Piers Blombery
Published in
Blood. Sep 01, 2026. Epub Sep 01, 2026.
Abstract
Genetic alterations activating NF‑κB have been described in mature B‑cell malignancies. These alterations include loss of the negative regulator TRAF3, allowing NIK (NF‑κB-inducing kinase) to drive non-canonical NF‑κB (ncNF‑κB) signaling. In this study, we characterized two recurrent synonymous variants of MAP3K14, the gene encoding NIK, across mature B‑cell malignancies including chronic lymphocytic leukemia, lymphoplasmacytic lymphoma/Waldenström'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‑κB 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‑κB activation, identifying candidate markers (e.g.,CD132/IL‑2Rγ) for assessing NF‑κB activation at a single cell level using flow cytometry. This study expands the spectrum of genetic lesions that result in activation of NF‑κB in mature B‑cell malignancies and highlights our incomplete understanding of NF‑κB drivers in mature B‑cell malignancies.
PMID:
42683823
Bibliographic data and abstract were imported from PubMed on 02 Sep 2026.
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