Strong constitutive NF-κB signaling in B cells drives SLL/CLL-like lymphomagenesis and overcomes microenvironmental dependencies
Year: 2026
Type: article
Abstract: 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.
Source: Leukemia
Authors: Valeria Soberón, Lena Osswald, Andrew Moore, Dominika Sosnowska, Gene Swinerd, Jingyu Chen, Seren Baygün, Carina Diehl, Gönül Seyhan, Laura Kraus, Vanessa Gölling, Ricarda Trapp, Thomas J. O’Neill, Sabrina Bortoluzzi, Daniel Kovacs, Tim Ammon, Pankaj Singroul, Yuliia Hubarzhevska, Rupert Öllinger, Sebastian Mueller, Olga Baranov, Piero Giansanti, Felix Gillhuber, Sonja Grath, Oliver Weigert, Andreas Rosenwald, Yoshiteru Sasaki, Klaus Rajewsky, Katja Steiger, Florian Bassermann, Roland Rad, Daniel Krappmann, Ingo Ringshausen, Marc Schmidt-Supprian
Institutions: Max Planck Institute of Biochemistry, Deutsches Konsortium für Translationale Krebsforschung, Technical University of Munich, University of Cambridge, University College London, Sichuan University, West China Medical Center of Sichuan University, Helmholtz Munich, TUM Klinikum, Ludwig-Maximilians-Universität München, University of Würzburg, Harvard University, Tohoku Medical and Pharmaceutical University, Max Delbrück Center, Max Planck Society
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $5,190
Awards: SFB 1243: Genetische und epigenetische Evolution von hämatopoetischen Neoplasien, Mechanistic and proteomic analyses of NFkappaBdriven lymphomas, G1784432850, G3343540213, G4135729386, G434337789, G4511069281, G4922147613, FOR 2033: Die hämatopoetischen Nischen, Post-transcriptional Regulation of Germinal Center B Cell Responses in Immunity and Disease, G6510036101, G6676355492, CoEvolution des Follikulären Lymphoms und seines Mikromilieus während der Krankheitsentstehung, Progression und Entwicklung von Therapieresistenzen, G7336389477, The analysis of mouse models in order to define the roles of IKK/NFKappaB and JNK signaling in lymphocyte physiology and pathology, Funktionelle Auswirkungen der MALT1‐Protease‐Aktivierung in der B‐Zell‐Lymphomagenese, G848503479
OpenAlex ID: W7124469645