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

nature cancer Article https://doi.org/10.1038/s43018-025-01093-z Targeting β-catenin degradation with GSK3β inhibitors induces cell death in acute lymphoblastic leukemia Received: 22 February 2025 Accepted: 10 November 2025 Published online: 8 January 2026 Check for updates Kadriye Nehir Cosgun1,15, Huda Jumaa2,15, Mark E. Robinson1, Zhangliang Cheng1,3, Salim Oulghazi1, Kohei Kume 1, David Fonseca Arce1, Nikol Agadzhanian1, Klaus M. Kistner4,5, Etienne Leveille1, Elsa Drivet 6,7, Fang Yu8, Zhijian Qian8, Joo Y. Song9, Wing-Chung Chan 9, Liang Xu8,14, Gang Xiao 8,14, M. Mark Taketo 10, Shalin Kothari1, Matthew S. Davids 11, Hilde Schjerven 6,7,12,13, Julia Jellusova 2,4,5,16 & Markus Müschen 1,3,16 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. The canonical Wnt–β-catenin pathway regulates fundamental processes including embryonic development, organogenesis and tissue homeostasis1. β-catenin protein degradation is initiated by phosphorylation of N-terminal β-catenin residues2 (S33, S37, T41 and S45) by glycogen synthase kinase 3B (GSK3β) and casein kinase 1α (CK1α) and the scaffolding proteins Axin1/2 and APC3,4, followed by ubiquitination5 and proteasomal degradation. Unphosphorylated β-catenin accumulates in nucleus6 and pairs with T cell factors (TCFs)7,8 to promote transcriptional activation of Wnt targets including MYC9,10. Transcriptional activation A full list of affiliations appears at the end of the paper. Nature Cancer | Volume 7 | January 2026 | 150–168 of MYC by TCF–β-catenin complexes represents a central oncogenic driver in multiple cancer types9,10. In contrast to epithelial, neuronal and mesenchymal lineages1, β-catenin deletion was dispensable for hematopoietic and B cell development11–14. Instead, targeted removal of GSK3β and CK1α phosphorylation sites to stabilize β-catenin(S33;S45)+/fl mice2 impaired hematopoietic multilineage differentiation and lymphoid development15,16. Conversely, in colon cancer, melanoma and other epithelial cancers, defective β-catenin protein degradation accelerated MYC-dependent proliferation and malignant transformation17–20. e-mail: 150 Article https://doi.org/10.1038/s43018-025-01093-z a Lung Colon Melanoma Mantle cell Follicular DLBCL Hodgkin’s 50 µm b Lung Colon Melanoma B-ALL DLBCL MCL Burkitt HD MM Nuclear 100 kDa β-catenin Colon SW480 2.0 Lung Colon Breast L428 U266 RAJI RAMOS GUMBUS KMH2 JEKO1 Z138 JJN3 mScarlet MCL JEKO Breast MCF10 DLBCL TMD8 β-catenin–GFP (protein) Follicular DLBCL 60 40 20 0 Hodgkin’s B-NHL Kidney HEK 80 B-ALL B-ALL TOM1 Melanoma MCL Ovary P2A Lung Squamous Colorectal Prostate Bladder Glioma Liver Kidney Endometrial Ovarian Pancreas Gastric Breast Lung Sarcoma Neuroendo Melanoma Myeloma Hodgkin’s B-cell, NOS DLBCL Mantle cell Burkitt’s B-ALL –2.5 Lung H82 Colon 0 GFP β-catenin B-ALL KOPN8 Normal Epithelial β-catenin protein Dual reporter construct Protein-to-mRNA ratio [%] 1.0 e β-catenin mRNA versus protein β-catenin-mScarlet (mRNA) 1.5 MINO Karpas-422 HBL-1 OCI-LY10 SU-DHL2 SU-DHL4 BLQ5 IAH8R ICN1 Epithelial B lymphoid 2.5 f SFO5 MXP5 M230 M229 DLD1 PDX2 MXP2 d β-catenin mRNA 2.5 RPPA[z score] M285 SW620 SW480 LOVO H526 HT-29 H69 H446 H524 HCT116 B lymphoid Epithelial, Mesenchymal 3.0 P = 2.23 × 10–8 RNA-seq TPM[log10] c H2444 TBP H82 β-tubulin 37 kDa H146 50 kDa β-catenin N-terminal phospho-β-catenin 200 µm g Lung Colon B-ALL MCL post-GC 100 kDa β-catenin N-terminal phospho-β-catenin 100 kDa 100 kDa Non-phospho β-catenin 50 kDa RAMOS TOLEDO REC1 Z138 LAX7 MXP2 PDX2 DLD1 HT116 LOVO H69 HT29 H82 β-actin Genetic mouse models of myeloid malignancies demonstrated that β-catenin was required for the initiation of acute myeloid leukemia (AML)21 and chronic myeloid leukemia (CML)22,23. However, the development of murine B cell acute lymphoblastic leukemia (B-ALL) was unperturbed by deletion of β-catenin23. Two studies on the effects of Wnt3A-dependent β-catenin accumulation on proliferation of B-ALL cells reported conflicting results24,25. B-ALL cells with TCF3–PBX1 fusion aberrantly overexpress the WNT16 ligand26. However, subsequent work showed that WNT16 does not promote canonical β-catenin signaling27. Here, we show that B-ALL cells have evolved and critically depend on high-efficiency mechanisms of β-catenin protein degradation (Extended Data Fig. 1a). GSK3β has a central role in mediating high-efficiency β-catenin protein degradation3,4. Small-molecule inhibitors of GSK3β have been developed for the treatment of solid tumors and neurological conditions (Extended Data Fig. 1b)28–33. While these small-molecule inhibitors Nature Cancer | Volume 7 | January 2026 | 150–168 achieved favorable safety profiles in early-phase clinical trials, our preclinical experiments provide a rationale to repurpose these existing GSK3β inhibitors to subvert β-catenin protein degradation to improve outcomes for persons with refractory B cell malignancies. Results Lack of β-catenin protein expression in B cell malignancies Studying β-catenin protein levels by immunohistochemistry in normal lymphoid tissues (n = 30) in comparison to epithelial and mesenchymal tissues (n = 51) (Extended Data Fig. 2a,b)34 (https://www.proteinatlas. org/) as well as lung cancer (n = 15), colon cancer (n = 25), malignant melanoma (n = 5) in comparison to mantle cell lymphoma (MCL; n = 26), follicular lymphoma (n = 38), diffuse large B cell lymphoma (DLBCL; n = 35) and Hodgkin’s disease (HD; n = 44), revealed a previously unrecognized lack of β-catenin protein expression in normal and malignant 151 Article https://doi.org/10.1038/s43018-025-01093-z Fig. 1 | B lymphoid cells express β-catenin mRNA but lack β-cateni (...truncated)