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Lesions of the \u03b2-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 \u03b2-catenin protein degradation. Compared to solid tumors, we found that mouse and human B-ALL express \u03b2-catenin protein at much lower levels; \u03b2-catenin protein was constitutively phosphorylated by glycogen synthase kinase 3B (GSK3\u03b2) and poised for proteasomal degradation. Instead of TCF\u2013\u03b2-catenin complexes to activate MYC, \u03b2-catenin paired with B lymphoid Ikaros and NuRD complex factors, resulting in MYC repression and acute cell death. To leverage \u03b2-catenin protein degradation as a previously unrecognized vulnerability in B-ALL, we validated GSK3\u03b2 inhibition in patient-derived xenograft models in vivo. CRISPR screens confirmed \u03b2-catenin protein degradation as a central mechanistic target of established GSK3\u03b2 inhibitors. As several GSK3\u03b2 inhibitors achieved favorable safety profiles in clinical trials, our results provide a rationale for repurposing these compounds for persons with refractory B cell malignancies.<\/jats:p>","DOI":"10.1038\/s43018-025-01093-z","type":"journal-article","created":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T10:03:03Z","timestamp":1767866583000},"page":"150-168","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Targeting \u03b2-catenin degradation with GSK3\u03b2 inhibitors induces cell death in acute lymphoblastic leukemia"],"prefix":"10.1038","volume":"7","author":[{"given":"Kadriye Nehir","family":"Cosgun","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huda","family":"Jumaa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark E.","family":"Robinson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhangliang","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salim","family":"Oulghazi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2856-5970","authenticated-orcid":false,"given":"Kohei","family":"Kume","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Fonseca Arce","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikol","family":"Agadzhanian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klaus M.","family":"Kistner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Etienne","family":"Leveille","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-3481-4071","authenticated-orcid":false,"given":"Elsa","family":"Drivet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhijian","family":"Qian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joo Y.","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6243-6008","authenticated-orcid":false,"given":"Wing-Chung","family":"Chan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9476-3847","authenticated-orcid":false,"given":"Gang","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9032-4505","authenticated-orcid":false,"given":"M. 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