The Role And Mechanism Of STAT3 Inhibitor Bp-1-102 In T-cell Acute Lymphoblastic Leukemia

Background: Originating from the malignant transformation of T progenitor cells,T-cell acute lymphoblastic leukemia is a kind of hematological malignancies with marked heterogeneity.The drug resistance and recurrence of T-ALL remains a serious problem to the physicians.Therefore,the development and screening of effective targeted drugs still have important clinical significance.JAK-STAT pathway is constitutively activated in hematological tumors,and STAT3 becomes a potential therapeutic target for T-ALL.With proven safety and efficacy in several kinds of solid tumors,BP-1-102 emerges as a specific inhibitor of STAT3 phosphorylation.The role and mechanism of BP-1-102 in T-ALL deserves further study.Objective: To explore various anti-tumor effects of small molecule inhibitor BP-1-102 on T-ALL cells and correspongding biological mechanism.Methods: In the current study,T-ALL cell lines MOLT-4,CUTLL1 and JURKAT cell lines were used as the research objects.A gradient concentration of BP-1-102 were administered onto the T-ALL cells and incubated for 6～48 hours.The effects of BP-1-102 on cell proliferation and colony formation were detected by CCK-8 assay and clone formation assay respectively.Cell cycle distribution and apoptosis rates were determined by PI single staining and Annexin V+PI double staining respectively.The morphological changes of autophagy and apoptosis were observed by inverted light microscope and transmission electron microscope.The expression changes of proteins such as JAK2-STAT3 pathway,c-Myc,Bclx L,Bcl-2,cyclin D1 and LC3 B were determined by western blotting.Results: BP-1-102 inhibited the proliferation and colony formation of MOLT-4 and CUTLL1 cell lines.BP-1-102 can significantly induce apoptosis and initiate autophagy in MOLT-4 and CUTLL1 cell lines,as well as result in cell cycle arrest in G0/G1 phase.BP-1-102 can suppress JAK2-STAT3 pathway and down-regulate the expression of its downstream proteins such as c-Myc.Conclusion: BP-1-102 can suppress the JAK2-STAT3 signaling pathway in T-ALL cells and exert various anti-tumor effects,emerging as a promising targeted anti-tumor inhibitor.