BETA (β) catenin degradation has been identified as a critical and previously unrecognised vulnerability in B cell acute lymphoblastic leukaemia, offering a potential new therapeutic strategy for refractory disease.
Beta Catenin Degradation in B Cell Malignancy
Canonical Wnt signalling is typically associated with cancer cell proliferation through T cell factor and beta catenin complexes that activate MYC dependent transcription. In many solid tumours, oncogenic mutations disrupt the beta catenin protein degradation machinery, leading to sustained signalling and uncontrolled growth. However, the present study demonstrates that B cell acute lymphoblastic leukaemia lacks these lesions and instead relies on intact beta catenin degradation for survival.
Researchers showed that both mouse and human B cell acute lymphoblastic leukaemia expressed markedly lower beta catenin protein levels compared with solid tumours. Beta catenin protein was constitutively phosphorylated by glycogen synthase kinase 3 beta and primed for proteasomal degradation. This finding indicates a fundamentally different role for beta catenin in B cell malignancy compared with other cancer types.
Altered MYC Regulation and Cell Survival
Rather than forming transcriptionally active complexes with T cell factor, beta catenin in B cell acute lymphoblastic leukaemia interacted with B lymphoid Ikaros and nucleosome remodelling and deacetylase complex factors. This interaction resulted in repression of MYC expression and led to acute cell death when beta catenin degradation was disrupted. These data underline the importance of beta catenin degradation in maintaining leukaemia cell viability.
CRISPR screening approaches further confirmed that beta catenin protein degradation represents a central mechanistic target of established glycogen synthase kinase 3 beta inhibitors. This genetic validation strengthens the mechanistic link between kinase inhibition and leukaemia cell death.
Therapeutic Implications of GSK3β Inhibition
To translate these findings into a therapeutic context, the researchers evaluated glycogen synthase kinase 3 beta inhibition in patient derived xenograft models in vivo. Inhibition of this kinase effectively leveraged beta catenin degradation as a vulnerability, supporting its potential as a treatment strategy.
Importantly, several glycogen synthase kinase 3 beta inhibitors have already demonstrated favourable safety profiles in clinical trials for other indications. The study therefore provides a rationale for repurposing these compounds for patients with refractory B cell malignancies, with beta catenin degradation emerging as a promising and targetable pathway in B cell acute lymphoblastic leukaemia.
Reference
Cosgun KN et al. Targeting β-catenin degradation with GSK3β inhibitors induces cell death in acute lymphoblastic leukemia. Nature Cancer. 2026; https://doi.org/10.1038/s43018-025-01093-z.
