DHX15 is associated with poor prognosis in acute myeloid leukemia (AML) and regulates cell apoptosis via the NF-kB signaling pathway.
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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DHX15 与急性髓系白血病 (AML) 的不良预后相关，并通过 NF-kB 信号通路调节细胞凋亡。
DOI：
10.18632/oncotarget.20288
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发表时间：
2017-10-27
期刊：
影响因子：
--
通讯作者：
Wang SY
中科院分区：
文献类型：
--
作者：
Pan L;Li Y;Zhang HY;Zheng Y;Liu XL;Hu Z;Wang Y;Wang J;Cai YH;Liu Q;Chen WL;Guo Y;Huang YM;Qian F;Jin L;Wang J;Wang SY
DHX 15是一种新发现的DEAH盒RNA解旋酶，其在白血病发生中的作用尚不清楚。在此，我们鉴定了DHX 15中的复发突变（NM_001358：c.664C>G：p.（R222 G））和4/240例散发性AML患者。此外，DHX 15通常在AML患者中过表达，并与较差的总生存期（OS）（P=0.019）和无复发生存期（RFS）（P=0.032）相关。此外，我们发现了DHX 15的独特表达模式。DHX 15在造血干细胞和白血病细胞中高表达，而在成熟血细胞中低表达。当AML患者达到疾病缓解或白血病细胞系被诱导分化时，DHX 15下调。DHX 15沉默显著抑制白血病细胞增殖，诱导细胞凋亡和G1期阻滞。相反，DHX 15表达的恢复挽救了细胞活力并减少了细胞凋亡。此外，我们发现，DHX 15下调时，细胞凋亡诱导的ATO（三氧化二砷）; DHX 15的过度表达引起显着的抵抗ATO诱导的细胞凋亡，表明DHX 15在细胞凋亡中的重要作用。我们进一步探讨了DHX 15在细胞凋亡中的作用机制，发现过表达DHX 15可激活NF-κ B的转录。DHX 15的敲低抑制白血病细胞核转位和NF-κ B亚单位P65的活化。NF-kB通路的几个下游靶点也被下调，并且凋亡相关基因CASP 3和PARP被激活。总之，本研究首次证明DHX 15通过NF-κ B信号通路在白血病发生中起重要作用，并可作为AML的独立预后标志物。
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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影响因子：
30.8
作者：
Faber ZJ;Chen X;Gedman AL;Boggs K;Cheng J;Ma J;Radtke I;Chao JR;Walsh MP;Song G;Andersson AK;Dang J;Dong L;Liu Y;Huether R;Cai Z;Mulder H;Wu G;Edmonson M;Rusch M;Qu C;Li Y;Vadodaria B;Wang J;Hedlund E;Cao X;Yergeau D;Nakitandwe J;Pounds SB;Shurtleff S;Fulton RS;Fulton LL;Easton J;Parganas E;Pui CH;Rubnitz JE;Ding L;Mardis ER;Wilson RK;Gruber TA;Mullighan CG;Schlenk RF;Paschka P;Döhner K;Döhner H;Bullinger L;Zhang J;Klco JM;Downing JR
通讯作者：
Downing JR
影响因子：
3.5
作者：
Niu, Zhaoyang;Jin, Wenxing;Li, Xialu
通讯作者：
Li, Xialu
影响因子：
11.2
作者：
Farrar JE;Schuback HL;Ries RE;Wai D;Hampton OA;Trevino LR;Alonzo TA;Guidry Auvil JM;Davidsen TM;Gesuwan P;Hermida L;Muzny DM;Dewal N;Rustagi N;Lewis LR;Gamis AS;Wheeler DA;Smith MA;Gerhard DS;Meshinchi S
通讯作者：
Meshinchi S
影响因子：
7.3
作者：
Albrecht, B;Hausmann, M;Walch, A
通讯作者：
Walch, A
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影响因子：
8
作者：
Lin S;Tian L;Shen H;Gu Y;Li JL;Chen Z;Sun X;You MJ;Wu L
通讯作者：
Wu L