Using BiP Inducer X to target the unfolded protein response (UPR) for T-cell acute lymphoblastic leukaemia (T-ALL) treatment

Introduction
The unfolded protein response (UPR) is essential for maintaining cellular homeostasis by resolving protein-folding imbalances within the endoplasmic reticulum (ER). In T-cell acute lymphoblastic leukemic cells, the induction of the UPR supports survival and progression of the malignancy, presenting a potential therapeutic vulnerability. This study evaluates BiP inducer X (BIX), a UPR modulator, as a treatment for T-cell acute lymphoblastic leukemia (T-ALL).

Materials and Methods
T-cell acute lymphoblastic leukemic cell lines (Jurkat, MOLT-4, CUTLL-1) were treated with BIX, and apoptosis was assessed via flow cytometry and caspase activity assays. UPR markers, including BiP, CHOP, ATF4, and ATF6, were analyzed using Western blotting and/or qPCR. In vivo toxicity and efficacy of BIX were tested in a T-ALL mouse model by monitoring blood counts, liver function, and leukemic progression.

Results and Discussion
BIX treatment induced caspase-dependent apoptosis in T-ALL cell lines without affecting non-hematopoietic cells. BIX- induced apoptosis was ATF6-pathway dependent and independent of BiP, CHOP, and ATF4 modulation, suggesting a distinct mechanism of action. In vivo, BIX was non-toxic and selectively induced apoptosis in leukemic cells, with no adverse effects on blood or liver parameters. These findings demonstrate BIX`s targeted ability to disrupt the UPR, effectively inducing cell death in T-ALL cells.

Conclusions
This study identifies BIX as a promising therapeutic candidate for T-ALL, leveraging the leukemic cells` sensitivity to UPR disruption. The ATF6 cleavage inhibition by BIX opens avenues for further research into its mechanism of action, supporting clinical translation as a targeted, low-toxicity treatment for T-ALL