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.