Kadriye Nehir Cosgun, Huda Jumaa, Mark E. Robinson, Zhangliang Cheng, Salim Oulghazi, Kohei Kume, David Fonseca Arce, Nikol Agadzhanian, Klaus M. Kistner, Etienne Léveillé, Elsa Drivet, Fang Yu, Zhijian Qian, Joo Y. Song, Wing-Chung Chan, Liang Xu, Gang Xiao, M. Mark Taketo, Shalin Kothari, Matthew S. Davids, Hilde Schjerven, Julia Jellusova, Markus Müschen
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 degradation as a previously unrecognized vulnerability in B-ALL, we validated GSK3β inhibition in patient-derived xenograft models in vivo. CRISPR screens confirmed β-catenin protein degradation as a central mechanistic target of established GSK3β inhibitors. As several GSK3β inhibitors achieved favorable safety profiles in clinical trials, our results provide a rationale for repurposing these compounds for persons with refractory B cell malignancies.