DHX9-mediated pathway contributes to the malignant phenotype of myelodysplastic syndromes

Nanfang Huang; Yang Song; Wenhui Shi; Juan Guo; Zheng Zhang; Qi He; Lingyun Wu; Xiao Li; Feng Xu

doi:10.1016/j.isci.2023.106962

DHX9-mediated pathway contributes to the malignant phenotype of myelodysplastic syndromes

iScience. 2023 May 25;26(6):106962. doi: 10.1016/j.isci.2023.106962. eCollection 2023 Jun 16.

Authors

Nanfang Huang¹, Yang Song¹, Wenhui Shi¹, Juan Guo¹, Zheng Zhang¹, Qi He¹, Lingyun Wu¹, Xiao Li¹, Feng Xu¹

Affiliation

¹ Department of Hematology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China.

Abstract

DHX9 is a member of the DEAH (Asp-Glu-Ala-His) helicase family and regulates DNA replication and RNA processing. DHX9 dysfunction promotes tumorigenesis in several solid cancers. However, the role of DHX9 in MDS is still unknown. Here, we analyzed the expression of DHX9 and its clinical significance in 120 MDS patients and 42 non-MDS controls. Lentivirus-mediated DHX9-knockdown experiments were performed to investigate its biological function. We also performed cell functional assays, gene microarray, and pharmacological intervention to investigate the mechanistic involvement of DHX9. We found that overexpression of DHX9 is frequent in MDS and associated with poor survival and high risk of acute myeloid leukemia (AML) transformation. DHX9 is essential for the maintenance of malignant proliferation of leukemia cells, and DHX9 suppression increases cell apoptosis and causes hypersensitivity to chemotherapeutic agents. Besides, knockdown of DHX9 inactivates the PI3K-AKT and ATR-Chk1 signaling, promotes R-loop accumulation, and R-loop-mediated DNA damage.

Keywords: Cancer; Medical Microbiology; Pathophysiology.