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| Item Type: | Article |
|---|---|
| Title: | Strong constitutive NF-κB signaling in B cells drives SLL/CLL-like lymphomagenesis and overcomes microenvironmental dependencies |
| Creators Name: | Soberón, Valeria, Osswald, Lena, Moore, Andrew, Sosnowska, Dominika, Swinerd, Gene, Chen, Jingyu, Baygün, Seren, Diehl, Carina, Seyhan, Gönül, Kraus, Laura, Gölling, Vanessa, Trapp, Ricarda, O'Neill, Thomas J., Bortoluzzi, Sabrina, Kovacs, Daniel, Ammon, Tim, Singroul, Pankaj, Hubarzhevska, Yuliia, Öllinger, Rupert, Mueller, Sebastian, Baranov, Olga, Giansanti, Piero, Gillhuber, Felix, Grath, Sonja, Weigert, Oliver, Rosenwald, Andreas, Sasaki, Yoshiteru, Rajewsky, Klaus, Steiger, Katja, Bassermann, Florian, Rad, Roland, Krappmann, Daniel, Ringshausen, Ingo and Schmidt-Supprian, Marc |
| 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 |
| ISSN: | 0887-6924 |
| Publisher: | Nature Publishing Group |
| Date: | 16 January 2026 |
| Additional Information: | Accessions "GSE289013" and "GSE289016" are currently private and are scheduled to be released on Feb 07, 2029. ProteomeXchange dataset PXD069904 has been reserved by the PRIDE repository for a dataset that has been deposited, but is not yet publicly released and announced to ProteomeXchange. |
| Official Publication: | https://doi.org/10.1038/s41375-025-02844-8 |
| PubMed: | View item in PubMed |
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