Connexin 43 promotes stemness of leukemia cells and chemoresistance in T-cell acute lymphoblastic leukemia via the RAC1/AKT/GSK3β axis.

BACKGROUND

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy that remains a clinical challenge because of drug resistance and relapse, necessitating deeper insights into the mechanism of leukemogenesis and progression. Connexin 43 (CX43) modulates tumor growth and metastasis by regulating cell-extracellular matrix interactions and the tumor microenvironment, but its role in T-ALL remains unclear. The study aims to investigate the changes in the expression of CX43 in the context of T-ALL, its effect on patient prognosis, and the underlying mechanisms.

METHODS

To investigate the impact of CX43 on survival and relapse, this study retrieved databases to analyze the differential expression of CX43 between patients with T-ALL and healthy individuals, as well as its prognostic implications. Meanwhile, the CX43-overexpressing (CX43OE) and neurogenic locus notch homolog protein 1 (Notch1)-mutant plasmids were used to develop a primary T-ALL knock-in mouse model and investigate the effects of CX43 on T-ALL in vitro and in vivo.

RESULTS

The overexpression of CX43 significantly promoted the development and progression of T-ALL and suppressed apoptosis by increasing the stemness of T-ALL cells through the upregulation of Rac family small GTPase 1 (RAC1) expression and the promotion of the phosphorylation of the protein kinase B (AKT)/glycogen synthase kinase 3 beta (GSK3β) pathway. Targeting the AKT/GSK3β axis attenuated the stemness induced by CX43 overexpression.

CONCLUSION

These findings suggest that targeting CX43-mediated pathways may help overcome leukemia stem cell-driven relapse and improve treatment outcomes in patients with T-ALL.