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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: |
Soberón, Valeria, Osswald, Lena, Moore, Andrew, Sosnowska, Dominika, Swinerd, Gene  ORCID: https://orcid.org/0000-0001-9644-9109, Chen, Jingyu, Baygün, Seren ORCID: https://orcid.org/0000-0002-3198-7632, Diehl, Carina, Seyhan, Gönül ORCID: https://orcid.org/0000-0002-3879-8009, Kraus, Laura, Gölling, Vanessa, Trapp, Ricarda, O'Neill, Thomas J. ORCID: https://orcid.org/0000-0003-2253-3118, Bortoluzzi, Sabrina, Kovacs, Daniel, Ammon, Tim, Singroul, Pankaj ORCID: https://orcid.org/0000-0001-9855-1828, Hubarzhevska, Yuliia, Öllinger, Rupert ORCID: https://orcid.org/0000-0002-2292-5982, Mueller, Sebastian ORCID: https://orcid.org/0009-0008-1514-3027, Baranov, Olga, Giansanti, Piero ORCID: https://orcid.org/0000-0003-2857-0841, Gillhuber, Felix ORCID: https://orcid.org/0009-0007-9271-4340, Grath, Sonja ORCID: https://orcid.org/0000-0003-3621-736X, Weigert, Oliver ORCID: https://orcid.org/0000-0002-0987-7373, Rosenwald, Andreas, Sasaki, Yoshiteru, Rajewsky, Klaus ORCID: https://orcid.org/0000-0002-6633-6370, Steiger, Katja ORCID: https://orcid.org/0000-0002-7269-5433, Bassermann, Florian ORCID: https://orcid.org/0000-0003-4435-2609, Rad, Roland ORCID: https://orcid.org/0000-0002-6849-9659, Krappmann, Daniel ORCID: https://orcid.org/0000-0001-7640-3234, Ringshausen, Ingo and Schmidt-Supprian, Marc ORCID: https://orcid.org/0000-0002-8543-6166
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| 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. |
| Keywords: | B-Cell Chronic Lymphocytic Leukemia, B-Lymphocytes, I-Kappa B Kinase, Inbred C57BL Mice, NF-Kappa B, Signal Transduction, Tumor Microenvironment, Animals, Mice |
| Source: | Leukemia |
| ISSN: | 0887-6924 |
| Publisher: | Nature Publishing Group |
| Volume: | 40 |
| Number: | 3 |
| Page Range: | 522-539 |
| Date: | March 2026 |
| Additional Information: | Erratum in: Leukemia, 2026 Feb 11. - Accessions "GSE289013" and "GSE289016" are currently private and are scheduled to be released on Feb 07, 2029. |
| Official Publication: | https://doi.org/10.1038/s41375-025-02844-8 |
| PubMed: | View item in PubMed |
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