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Soberón, V.* ; Osswald, L.* ; Moore, A.* ; Sosnowska, D.* ; Swinerd, G.* ; Chen, J.* ; Baygün, S.* ; Diehl, C.* ; Seyhan, G.* ; Kraus, L.* ; Gölling, V.* ; Trapp, R.* ; O'Neill, T.J. ; Bortoluzzi, S.* ; Kovacs, D.* ; Ammon, T.* ; Singroul, P.* ; Hubarzhevska, Y.* ; Öllinger, R.* ; Mueller, S.* ; Baranov, O.* ; Giansanti, P.* ; Gillhuber, F.* ; Grath, S.* ; Weigert, O.* ; Rosenwald, A.* ; Sasaki, Y.* ; Rajewsky, K.* ; Steiger, K.* ; Bassermann, F.* ; Rad, R.* ; Krappmann, D. ; Ringshausen, I.* ; Schmidt-Supprian, M.*

Strong constitutive NF-κB signaling in B cells drives SLL/CLL-like lymphomagenesis and overcomes microenvironmental dependencies.

Leukemia 40, 522–539 (2026)
Verlagsversion Forschungsdaten DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
Aberrant activation of NF-κB transcription factors is a hallmark of human lymphomas. Most lymphoma-intrinsic as well as microenvironment-induced NF-κB activation occurs upstream of the key kinase IKK2, therefore affecting additional pathways. Here, we show that canonical NF-κB signaling in mouse B cells, induced through the expression of one or two copies of a constitutively active IKK2 variant, dose-dependently drives lymphomagenesis. The observed phenotype and stereotypic B cell receptor clonality resemble human small lymphocytic lymphoma (SLL) and chronic lymphocytic leukemia (CLL). Stronger IKK2 signaling drives early B1a cell expansion and uniform SLL/CLL-like lymphomagenesis, while intermediate signals cause more heterogeneous malignancies. Mechanistically, constitutive IKK2 signals provide a profound cell-intrinsic competitive advantage to B1a cells and dose-dependently synergize with TCL1 overexpression in driving aggressive CLL. Further, strong constitutive NF-κB activation overcomes critical microenvironmental dependencies of TCL1-driven lymphomas. Our findings establish canonical NF-κB as an oncogenic driver in lymphoma and reveal reduced microenvironment dependency as a key NF-κB-mediated mechanism, thus highlighting its therapeutic relevance.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Chronic Lymphocytic-leukemia; Tumor-necrosis-factor; Germinal Center; Activation; Mouse; Expression; Multiple; Receptor; Baff; Proliferation
ISSN (print) / ISBN 0887-6924
e-ISSN 1476-5551
Zeitschrift Leukemia
Quellenangaben Band: 40, Heft: , Seiten: 522–539 Artikelnummer: , Supplement: ,
Verlag Springer
Verlagsort Campus, 4 Crinan St, London, N1 9xw, England
Begutachtungsstatus Peer reviewed
Institut(e) Research Unit Signaling and Translation (SAT)
Förderungen Cancer Research UK (CRUK)
EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)
Deutsche Forschungsgemeinschaft (German Research Foundation)