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

## TL;DR

Strong NF-κB signaling in B cells causes SLL/CLL-like lymphomas and reduces reliance on the tumor environment.

## Contribution

This study identifies constitutive NF-κB signaling as a driver of lymphomagenesis and shows it reduces microenvironmental dependencies.

## Key findings

- Constitutive IKK2 signaling in B cells dose-dependently induces SLL/CLL-like lymphomas.
- Strong NF-κB activation provides a competitive advantage to B1a cells and synergizes with TCL1 overexpression.
- NF-κB signaling reduces the need for microenvironmental support in TCL1-driven lymphomas.

## 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.