Targeting β-catenin degradation with GSK3β inhibitors induces cell death in acute lymphoblastic leukemia.

ABSTRACT: As part of canonical Wnt signaling, T cell factor (TCF)-β-catenin complexes promote MYC-dependent proliferation. Lesions of the β-catenin protein degradation machinery are common oncogenic drivers. Here, we show that B cell acute lymphoblastic leukemia (B-ALL) lacks these mutations and critically depends on unencumbered β-catenin protein degradation. Compared to solid tumors, we found that mouse and human B-ALL express β-catenin protein at much lower levels; β-catenin protein was constitutively phosphorylated by glycogen synthase kinase 3B (GSK3β) and poised for proteasomal degradation. Instead of TCF-β-catenin complexes to activate MYC, β-catenin paired with B lymphoid Ikaros and NuRD complex factors, resulting in MYC repression and acute cell death. To leverage β-catenin protein degradat

SUBMITTER: Cosgun KN 

PROVIDER: S-EPMC12858398 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature