Transcriptomic changes in response to inducible CTNNB1 activation in murine B-ALL cells

As part of canonical WNT signaling, TCF7/β-catenin-complexes promote MYC-dependent proliferation. Compared to solid tumors, we found that B-cell acute lymphoblastic leukemia (B-ALL) cells, express β-catenin protein at 80- to 200-fold lower levels and critically depend on its efficient degradation: β-catenin protein was constitutively phosphorylated by GSK3B and poised for proteasomal degradation. Lesions of the β-catenin-protein degradation machinery are common oncogenic drivers, however, B-ALL cells lacked these mutations and critically depend on unencumbered β-catenin-protein degradation. Instead of TCF7/β-catenin-complexes to activate MYC, β-catenin paired with B-lymphoid Ikaros factors, resulting in MYC-repression and acute cell death. To leverage β-catenin-protein degradation as previously unrecognized vulnerability in B-ALL, we validated GSK3B-inhibition in patient-derived xenograft models in vivo. CRISPR/Cas9 chemogenomic screens confirmed β-catenin protein degradation as central mechanistic target of established GSK3B-inhibitors. Based on favorable safety profiles in clinical trials, our results provide a rationale for repurposing existing GSK3B-inhibitors for patients with refractory B-cell malignancies. RNAseq in BCR-ABL1+ transformed murine pre-B with or without induction of beta-catenin activation using a CTNNB1 exon3 floxed model