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

Abstract

The role of <i>DHX15</i>, a newly identified DEAH-box RNA helicase, in leukemogenesis remains elusive. Here, we identified a recurrent mutation in <i>DHX15</i> (NM_001358:c.664C>G: p.(R222G)) in one familial AML patient and 4/240 sporadic AML patients. Additionally, <i>DHX15</i> 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 <i>DHX15</i>. <i>DHX15</i> was highly expressed in hematopoietic stem cells and leukemia cells but was lowly expressed in mature blood cells. <i>DHX15</i> was down-regulated when AML patients achieved disease remission or when leukemia cell lines were induced to differentiate. <i>DHX15</i> silencing greatly inhibited leukemia cell proliferation and induced cell apoptosis and G1-phase arrest. In contrast, the restoration of <i>DHX15</i> 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 <i>DHX15</i> activated <i>NF-kB</i> transcription. Knockdown of <i>DHX15</i> 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 <i>CASP3</i> and <i>PARP</i> were activated. In conclusion, this study represents the first demonstration that <i>DHX15</i> plays an important role in leukemogenesis via the NF-kB signaling pathway and may serve as an independent prognostic marker for AML.