STAT3 induces the expression of GLI1 in chronic lymphocytic leukemia cells
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Uri Rozovski1,2, David M. Harris1, Ping Li1, Zhiming Liu1, Preetesh Jain1, Taghi Manshouri1, Ivo Veletic1, Alessandra Ferrajoli1, Prithviraj Bose1, Phillip Thompson1, Nitin Jain1, Srdan Verstovsek1, William Wierda1, Michael J. Keating1 and Zeev Estrov1
1 Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
2 Division of Hematology, Davidoff Cancer Center, Rabin Medical Center, Petach Tiqva, and The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
|Zeev Estrov,||email:||[email protected]|
Keywords: CLL; STAT3; GLI1; apoptosis; transcription
Received: October 02, 2020 Accepted: January 26, 2021 Published: March 02, 2021
The glioma associated oncogene-1 (GLI1), a downstream effector of the embryonic Hedgehog pathway, was detected in chronic lymphocytic leukemia (CLL), but not normal adult cells. GLI1 activating mutations were identified in 10% of patients with CLL. However, what induces GLI1 expression in GLI1-unmutated CLL cells is unknown. Because signal transducer and activator of transcription 3 (STAT3) is constitutively activated in CLL cells and sequence analysis detected putative STAT3-binding sites in the GLI1 gene promoter, we hypothesized that STAT3 induces the expression of GLI1. Western immunoblotting detected GLI1 in CLL cells from 7 of 7 patients, flow cytometry analysis confirmed that CD19+/CD5+ CLL cells co-express GLI1 and confocal microscopy showed co-localization of GLI1 and phosphorylated STAT3. Chromatin immunoprecipitation showed that STAT3 protein co-immunoprecipitated GLI1 as well as other STAT3-regulated genes. Transfection of CLL cells with STAT3-shRNA induced a mark decrease in GLI1 levels, suggesting that STAT3 binds to and induces the expression of GLI1 in CLL cells. An electromobility shift assay confirmed that STAT3 binds, and a luciferase assay showed that STAT3 activates the GLI1 gene. Transfection with GLI1-siRNA significantly increased the spontaneous apoptosis rate of CLL cells, suggesting that GLI1 inhibitors might provide therapeutic benefit to patients with CLL.
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