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 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.

Codon bias confers stability to humanmRNAs

“…However, we acknowledge that our metric is only able to demonstrate a prediction to a limited extent. These obstacles for ribosome elongation are reversible and dynamically regulated by RNA helicases [56,57]. Taking into account our in vitro experiment results together with the ribosomal profiling results, we suggest that GC3 and AT3 codons are synonymous with optimal and non-optimal codons.…”

“…There is evidence to show that mRNA-intrinsic features that have the propensity to regulate ribosome velocity are essential in maintaining the function and correct expression of proteins, the failure of which may result in degradation of the mRNA and protein: Although codon optimality is a dominant factor in general, other factors may also be involved in decelerated ribosomes, such as secondary structures [54,55]. These obstacles for ribosome elongation are reversible and dynamically regulated by RNA helicases [56,57]. Importantly, these structures may serve to reduce ribosome speed when the nascent peptide requires additional time to fold to its correct conformation [58].…”

Diverse Roles of DEAD/DEAH-Box Helicases in Innate Immunity and Diseases

“…Similarly to DDX41, DHX15 has also been implied in the pathogenesis of acute myeloid leukemia (AML) [157]. The mutation of the highly conserved arginine significant for RNA binding (R222G) is related to AML, and the overexpression of DHX15 in the AML patients indicates poor cytogenic prognosis and overall survival [156,157].…”

“…Similarly to DDX41, DHX15 has also been implied in the pathogenesis of acute myeloid leukemia (AML) [157]. The mutation of the highly conserved arginine significant for RNA binding (R222G) is related to AML, and the overexpression of DHX15 in the AML patients indicates poor cytogenic prognosis and overall survival [156,157]. Of note, overexpressed DHX15 in AML acts through activation of NF-κB pathway just as during the viral infection, but it decreases the levels of caspase-3 and PARP, thereby promoting cell survival [157].…”

“…The mutation of the highly conserved arginine significant for RNA binding (R222G) is related to AML, and the overexpression of DHX15 in the AML patients indicates poor cytogenic prognosis and overall survival [156,157]. Of note, overexpressed DHX15 in AML acts through activation of NF-κB pathway just as during the viral infection, but it decreases the levels of caspase-3 and PARP, thereby promoting cell survival [157]. Considering that during the viral response DHX15 also activates apoptotic MAPK signaling, it is possible that DHX15 can activate NF-κB pathway independently of MAVS, or that the transformed myeloid cells in AML use aberrant MAVS signaling.…”