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Most lymphoma-intrinsic as well as microenvironment-induced NF-\u03baB activation occurs upstream of the key kinase IKK2, therefore affecting additional pathways. Here, we show that canonical NF-\u03baB 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-\u03baB activation overcomes critical microenvironmental dependencies of TCL1-driven lymphomas. Our findings establish canonical NF-\u03baB as an oncogenic driver in lymphoma and reveal reduced microenvironment dependency as a key NF-\u03baB-mediated mechanism, thus highlighting its therapeutic relevance.<\/jats:p>","DOI":"10.1038\/s41375-025-02844-8","type":"journal-article","created":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T08:53:51Z","timestamp":1768553631000},"page":"522-539","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Strong constitutive NF-\u03baB signaling in B cells drives SLL\/CLL-like lymphomagenesis and overcomes microenvironmental 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The work was supported by the DFG through project ID 452844127 to M.S.S. and O.W., project ID 514894665 to M.S.S., K.S., A.R. and F.B., project IDs 224805578, 278529602, 35879735,232863826 to M.S.S., the ERC under the European Union\u2019s Horizon 2020 research and innovation program (grant agreement 682435) to M.S.S. and Cancer Research UK grant C49940\/A17480 and DRCNPG-May23\/100006 to I.R.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}