-catenin engages IKZF factors to control lymphopoiesis

Abstract β-catenin-signaling promotes proliferation and survival in epithelial, neuronal, and mesenchymal lineages, but is dispensable for B- and T-cell development. β-catenin activation is a common oncogenic driver throughout all types of cancer with the exception of B- and T-lymphoid malignancies. Unlike epithelial tissues, we found that B- and T-cells consistently lack β-catenin expression. Instead, both B- and T-cells were highly sensitive to β-catenin-activation and critically depend on its negative regulation by GSK3β-dependent phosphorylation and degradation. Inhibition of GSK3β induced dramatic nuclear accumulation of β-catenin, anergy and cell death. In contrast, genetic deletion of β-catenin enabled clonal expansion of premalignant B- and T-cells. In epithelial cells, β-catenin and TCF-family factors form complexes for transcriptional activation of MYC. Instead of TCF-factors, our interactome studies in B- and T-cells revealed that, β-catenin formed complexes with lymphoid-specific Ikaros zinc finger (IKZF) transcription factors for transcriptional repressionof MYC at a recently discovered MYC ‘blood enhancer cluster’ (BENC). Hence, activation of β-catenin engages repressive complexes with Ikaros factors to regulate lymphopoiesis through transcriptional control of MYC. We propose that β-catenin-accumulation functions as sensing mechanism of pathological B- and T-cell signaling and that this mechanism can be leveraged for targeted eradication of pathological (autoreactive or malignant) clones. To engage this mechanism, targeted accumulation of β-catenin can be achieved by GSK3β-inhibition and represents a selective vulnerability of pathological B- and T-cell clones.