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

Lili Pan,Jiucun Wang,Li Jin,Xiao-Li Liu,Shao-Yuan Wang,Yang Li,Jing Wang,Wan-Ling Chen,Zheng Hu,Ying Guo,Hai-Ying Zhang,Feng Qian,Yi Wang,Qiao Liu,Yuan-Hua Cai,Yuan-Mao Huang,Yi Zheng

doi:10.18632/oncotarget.20288

Lili Pan, Jiucun Wang + Show 15 more

Open Access

https://doi.org/10.18632/oncotarget.20288

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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.

Highlights

RNA helicases are ubiquitous, highly conserved enzymes that participate in most aspects of RNA metabolism, including transcription, pre-mRNA splicing, mRNA export, ribosome biogenesis, translation and RNA degradation
We identified a recurrent mutation in DHX15 (NM_001358:c.664C>G:p. (R222G)) that was present in 4/240 sporadic cases (Figure 1A)
When aligning the amino acid sequence between human and other 10 species, we found that human DHX15 was a highly conserved protein, sharing 99%, 83% and 80% identities of the amino acid sequence with mouse, zebrafish, and yeast, respectively

Summary

Introduction

RNA helicases are ubiquitous, highly conserved enzymes that participate in most aspects of RNA metabolism, including transcription, pre-mRNA splicing, mRNA export, ribosome biogenesis, translation and RNA degradation. RNA helicases have received significant attention since their identification in the 1980s. Many RNA helicases are essential for cell viability, and a growing number of these enzymes have been implicated in carcinogenesis. RNA helicase DHX29 is overexpressed in various types of cancers,[2] and the down-regulation of DHX29 leads to impaired translation and suppression of cancer cell growth ex vivo and in vivo.[2] DDX5 is highly expressed in primary human T-ALL leukemia cells.[3] Knockdown of DDX5 results in reduced cell proliferation and increased apoptosis in cultured human leukemia cells and suppression of growth of human leukemia xenografts in nude mice.[3]

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