β-catenin engages IKZF factors to control lymphopoiesis

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