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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年1月8日

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  • Kadriye Nehir Cosgun,
  • Huda Jumaa,
  • Mark E. Robinson,
  • Zhangliang Cheng,
  • Salim Oulghazi,
  • Kohei Kume,
  • David Fonseca Arce,
  • Nikol Agadzhanian,
  • Klaus M. Kistner,
  • Etienne Leveille,
  • 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

摘要

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.