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

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; Schmidt-Supprian, Marc     «

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; Basserma...     »

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.     «

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 clona...     »