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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月16日

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  • 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

摘要

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.