DHX15 is associated with poor prognosis in acute myeloid leukemia (AML) and regulates cell apoptosis via the NF-kB signaling pathway
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Lili Pan1,2,*, Yang Li1,*, Hai-Ying Zhang2, Yi Zheng2, Xiao-Li Liu2, Zheng Hu2, Yi Wang3, Jing Wang2, Yuan-Hua Cai2, Qiao Liu2, Wan-Ling Chen2, Ying Guo2, Yuan-Mao Huang2, Feng Qian3, Li Jin3, Jiucun Wang3 and Shao-Yuan Wang1,2
1Fujian Institute of Hematology, Fujian Provincial Key Laboratory on Hematology, Department of Hematology, Fujian Medical University Union Hospital, Fuzhou, PR China
2Union Clinical Medical Colleges, Fujian Medical University, Fuzhou, PR China
3State 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
Shao-Yuan Wang, email: [email protected]
Jiucun Wang, email: [email protected]
Keywords: DHX15, AML, NF-kB, knockdown, overexpression
Received: May 09, 2017 Accepted: July 26, 2017 Published: August 16, 2017
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.
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