Daijiworld Media Network – New Delhi

New Delhi, Feb 3: Researchers have identified beta (β) catenin degradation as a critical and previously unrecognised vulnerability in B cell acute lymphoblastic leukaemia (B-ALL), opening the door to a potential new therapeutic strategy for patients with refractory disease.

The study found that unlike many solid tumours, B-ALL does not harbour oncogenic mutations that disrupt beta catenin degradation. Instead, leukaemia cells depend on an intact beta catenin degradation mechanism for survival. Both mouse and human B-ALL samples showed markedly lower beta catenin protein levels compared to solid tumours, with the protein being constitutively phosphorylated by glycogen synthase kinase 3 beta (GSK3β) and primed for proteasomal degradation.

Researchers observed that beta catenin in B-ALL does not activate cancer-promoting transcription through T cell factor complexes. Rather, it interacts with B lymphoid Ikaros and nucleosome remodelling and deacetylase complex factors, leading to repression of the MYC oncogene. Disruption of beta catenin degradation resulted in acute cell death, underscoring its importance in maintaining leukaemia cell viability.

CRISPR-based genetic screening further confirmed that beta catenin protein degradation is a key mechanistic target of established GSK3β inhibitors, strengthening the link between kinase inhibition and leukaemia cell death.

To assess therapeutic potential, the researchers tested GSK3β inhibition in patient-derived xenograft models, where it effectively exploited beta catenin degradation as a vulnerability. Notably, several GSK3β inhibitors have already shown favourable safety profiles in clinical trials for other diseases.

The findings provide strong justification for repurposing these inhibitors as a treatment option for refractory B cell malignancies, with beta catenin degradation emerging as a promising and targetable pathway in B cell acute lymphoblastic leukaemia.