Abstract
BackgroundT-cell acute lymphoblastic leukemia (T-ALL) is a highly aggressive hematologic malignancy. Immune tolerance induced by CD4+CD25+ regulatory T cells (Tregs) with high expression of Foxp3 is an important hypothesis for poor therapy response. Notch1 signaling is thought to be involved in the pathogenesis of this disease. Crosstalk between Notch and Foxp3+Tregs induced immune tolerance is unknown in T-ALL. We studied Foxp3 and Notch1 expression in vivo and in vitro, and analyzed the biological characteristics of T-ALL cell line systematically after Notch inhibition and explored the crosstalk between Notch signaling and Foxp3 expression.MethodsIn vivo, we established T-ALL murine model by Jurkat cells transplantation to severe combined immunodeficiency (SCID) mice. Notch1 and Foxp3 expression was detected. In vitro, we used γ-secretase inhibitor N-S-phenyl-glycine-t-butyl ester (DAPT) to block Notch1 signaling in Jurkat cells. Notch1, Hes-1 and Foxp3 genes and protein expression were detected by PCR and western blotting, respectively. The proliferation pattern, cell cycle and viability of Jurkat cells after DAPT treatment were studied. Protein expression of Notch1 target genes including NF-κB, p-ERK1/2 and STAT1 were determined.ResultsWe show that engraftment of Jurkat cells in SCID mice occurred in 8 of 10 samples (80%), producing disseminated human neoplastic lymphocytes in PB, bone marrow or infiltrated organs. Notch1 and Foxp3 expression were higher in T-ALL mice than normal mice. In vitro, Jurkat cells expressed Notch1 and more Foxp3 than normal peripheral blood mononuclear cells (PBMCs) in both mRNA and protein levels. Blocking Notch1 signal by DAPT inhibited the proliferation of Jurkat cells and induced G0/G1 phase cell cycle arrest and apoptosis. Foxp3 as well as p-ERK1/2, STAT1 and NF-κB expression was down regulated after DAPT treatment.ConclusionsThese findings indicate that regulation of Foxp3 expression does involve Notch signaling, and they may cooperatively regulate T cell proliferation in T-ALL.
Highlights
T-cell acute lymphoblastic leukemia (T-ALL) is a highly aggressive hematologic malignancy
The results showed that the percentage of Jurkat cells in the subG0/G1 phase increased significantly while in S and G2/M phase decreased (P < 0.05)
Blocking Notch1 signal by DAPT inhibits the proliferation of Jurkat cells To study the characteristics of Jurkat cells after DAPT treatment for 48 hours, cells were viewed under microscope
Summary
T-cell acute lymphoblastic leukemia (T-ALL) is a highly aggressive hematologic malignancy. The specific biological and molecular mechanisms that account for the aggressiveness and poor therapy response in T-ALL remain unclear and T-ALL cells induced immune. Notch is more and more concerned in T-ALL and activating mutations in the Notch gene are present in over 50% of human T-ALL cases making Notch the most prominent oncogene involved in the pathogenesis of this disease [2,3,9,10,11,12]. Zou J et al report that Notch is required for hypoxia-induced proliferation, invasion and chemoresistance of T-cell acute lymphoblastic leukemia cells [1,3,14,15,20,21,22,23]. Crosstalk between Notch and these pathways is incompletely understood and probably occurs at several levels
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