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DHX15 is associated with poor prognosis in acute myeloid leukemia (AML) and regulates cell apoptosis via the NF-kB signaling pathway

2017; Impact Journals LLC; Volume: 8; Issue: 52 Linguagem: Inglês

10.18632/oncotarget.20288

1949-2553

Lili Pan, Yang Li, Haiying Zhang, Yi Zheng, Xiaoli Liu, Wang Jian-hu, Yi Wang, Jing Wang, Yuanhua Cai, Qiao Liu, Wan-Ling Chen, Ying Guo, Yuanmao Huang, Feng Qian, Jin Li, Jiucun Wang, Shaoyuan Wang,

RNA regulation and disease

// Lili Pan 1, 2, * , Yang Li 1, * , Hai-Ying Zhang 2 , Yi Zheng 2 , Xiao-Li Liu 2 , Zheng Hu 2 , Yi Wang 3 , Jing Wang 2 , Yuan-Hua Cai 2 , Qiao Liu 2 , Wan-Ling Chen 2 , Ying Guo 2 , Yuan-Mao Huang 2 , Feng Qian 3 , Li Jin 3 , Jiucun Wang 3 and Shao-Yuan Wang 1, 2 1 Fujian Institute of Hematology, Fujian Provincial Key Laboratory on Hematology, Department of Hematology, Fujian Medical University Union Hospital, Fuzhou, PR China 2 Union Clinical Medical Colleges, Fujian Medical University, Fuzhou, PR China 3 State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, PR China * These authors have contributed equally to this work Correspondence to: Shao-Yuan Wang, email: shaoyuanwang@fjmu.edu.cn Jiucun Wang, email: jcwang@fudan.edu.cn Keywords: DHX15 , AML, NF-kB, knockdown, overexpression Received: May 09, 2017 Accepted: July 26, 2017 Published: August 16, 2017 ABSTRACT The role of DHX15 , a newly identified DEAH-box RNA helicase, in leukemogenesis remains elusive. Here, we identified a recurrent mutation in DHX15 (NM_001358:c.664C>G: p.(R222G)) in one familial AML patient and 4/240 sporadic AML patients. Additionally, DHX15 was commonly overexpressed in AML patients and associated with poor overall survival (OS) (P=0.019) and relapse-free survival (RFS) (P=0.032). In addition, we found a distinct expression pattern of DHX15 . DHX15 was highly expressed in hematopoietic stem cells and leukemia cells but was lowly expressed in mature blood cells. DHX15 was down-regulated when AML patients achieved disease remission or when leukemia cell lines were induced to differentiate. DHX15 silencing greatly inhibited leukemia cell proliferation and induced cell apoptosis and G1-phase arrest. In contrast, the restoration of DHX15 expression rescued cell viability and reduced cell apoptosis. In addition, we found that DHX15 was down-regulated when cell apoptosis was induced by ATO (arsenic trioxide); overexpression of DHX15 caused dramatic resistance to ATO-induced cell apoptosis, suggesting an important role for DHX15 in cell apoptosis. We further explored the mechanism of DHX15 in apoptosis and found that overexpression of DHX15 activated NF-kB transcription. Knockdown of DHX15 inhibited the nuclear translocation and activation of the NF-kB subunit P65 in leukemia cells. Several downstream targets of the NF-kB pathway were also down-regulated, and apoptosis-associated genes CASP3 and PARP were activated. In conclusion, this study represents the first demonstration that DHX15 plays an important role in leukemogenesis via the NF-kB signaling pathway and may serve as an independent prognostic marker for AML.