miR-181d/RBP2/NF-κB p65 Feedback Regulation Promotes Chronic Myeloid Leukemia Blast Crisis

Abstract

BackgroundChronic myeloid leukemia (CML) is a malignant clonal proliferative disease. Once it progresses into the phase of blast crisis (CML-BP), the curative effect is poor, and the fatality rate is extremely high. Therefore, it is urgent to explore the molecular mechanisms of blast crisis and identify new therapeutic targets.MethodsThe expression levels of miR-181d, RBP2 and NF-κB p65 were assessed in 42 newly diagnosed CML-CP patients and 15 CML-BP patients. Quantitative real-time PCR, Western blots, and cell proliferation assay were used to characterize the changes induced by overexpression or inhibition of miR-181d, RBP2 or p65. Luciferase reporter assay and ChIP assay was conducted to establish functional association between miR-181d, RBP2 and p65. Inhibition of miR-181d expression and its consequences in tumor growth was demonstrated in vivo models.ResultsWe found that miR-181d was overexpressed in CML-BP, which promoted leukemia cell proliferation. Histone demethylase RBP2 was identified as a direct target of miR-181d which downregulated RBP2 expression. Moreover, RBP2 inhibited transcriptional expression of NF-κB subunit, p65 by binding to its promoter and demethylating the tri/dimethylated H3K4 region in the p65 promoter locus. In turn, p65 directly bound to miR-181d promoter and upregulated its expression. Therefore, RBP2 inhibition resulting from miR-181d overexpression led to p65 upregulation which further forwarded miR-181d expression. This miR-181d/RBP2/p65 feedback regulation caused sustained NF-κB activation, which contributed to the development of CML-BP.ConclusionsTaken together, the miR-181d/RBP2/p65 feedback regulation promoted CML-BP and miR-181d may serve as a potential therapeutic target of CML-BP.

The Cross Marks the Spot: The Emerging Role of JmjC Domain-Containing Proteins in Myeloid Malignancies

“…However, little is known about the role of full-length, enzymatically active, KDM5A in myeloid malignancies. In chronic myelogenous leukemia (CML) blast phase (CML-BP), KDM5A plays an important role [ 44 , 45 ], bar one exception. MicroRNA-181d (miR-181d) is overexpressed in CML-BP, which directly targets and deregulates the expression of KMD5A.…”

“…Elevated KDM5A levels in turn inhibit the transcriptional repression of NF-kB subunit p65, a direct KDM5A target. The ensuing increase in NF-kB activation is further augmented by a positive feedback loop through binding of p65 to the miR-181d promoter [ 45 ]. This sustained activation suggests both miR-181d and KDM5A as potential therapeutic targets in CML-BP.…”

DNA methylation-mediated differential expression of DLX4 isoforms has opposing roles in leukemogenesis

“…reported the direct role of the miR-181 family in normal hematopoiesis and AML development [ 49 ]. Moreover, miR-181d /RBP2/NF-κB p65 feedback regulation promoted CML progression into blast crisis [ 50 ]. Additionally, Jang et al.…”

Bioinformatic Tools for the Analysis and Prediction of ncRNA Interactions

“…A well-documented example of a regulatory mechanism mediated by miRNAs, which function as modulator of transcripts of coding genes or their regulatory lncRNAs, involves PTEN, a tumor-suppressor gene under complex regulatory control by ncRNA [ 23 , 73 ]. The presence of mature miRNAs within the nucleus has also been reported; these miRNAs activate or silence genes through various mechanisms and, as a result of their direct interaction with DNA or through protein scaffolds ( Figure 3 D), mechanisms that include epigenetic pathways [ 74 , 75 , 76 ].…”