Abstract
Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by an excessive production of pro‐inflammatory cytokines resulting in chronic inflammation and genomic instability. Besides the driver mutations in JAK2,MPL, and CALR genes, the deregulation of miRNA expression may also contribute to the pathogenesis of PMF. To this end, we recently reported the upregulation of miR‐382‐5p in PMF CD34+ cells. In order to unveil the mechanistic details of the role of miR‐382‐5p in pathogenesis of PMF, we performed gene expression profiling of CD34+ cells overexpressing miR‐382‐5p. Among the downregulated genes, we identified superoxide dismutase 2 (SOD2), which is a predicted target of miR‐382‐5p. Subsequently, we confirmed miR‐382‐5p/SOD2 interaction by luciferase assay and we showed that miR‐382‐5p overexpression in CD34+ cells causes the decrease in SOD2 activity leading to reactive oxygen species (ROS) accumulation and oxidative DNA damage. In addition, our data indicate that inhibition of miR‐382‐5p in PMF CD34+ cells restores SOD2 function, induces ROS disposal, and reduces DNA oxidation. Since the pro‐inflammatory cytokine transforming growth factor‐β1 (TGF‐β1) is a key player in PMF pathogenesis, we further investigated the effect of TGF‐β1 on ROS and miR‐382‐5p levels. Our data showed that TGF‐β1 treatment enhances miR‐382‐5p expression and reduces SOD2 activity leading to ROS accumulation. Finally, inhibition of TGF‐β1 signaling in PMF CD34+ cells by galunisertib significantly reduced miR‐382‐5p expression and ROS accumulation and restored SOD2 activity. As a whole, this study reports that TGF‐β1/miR‐382‐5p/SOD2 axis deregulation in PMF cells is linked to ROS overproduction that may contribute to enhanced oxidative stress and inflammation. Our results suggest that galunisertib may represent an effective drug reducing abnormal oxidative stress induced by TGF‐β1 in PMF patients.Database linkingGEO: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE103464.
Highlights
Classical Philadelphia-negative chronic myeloproliferative neoplasms (MPNs) are clonal disorders of hematopoietic stem cell that include essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF; Vardiman et al, 2009) (Arber et al, 2016)
Primary myelofibrosis CD34+ cells were isolated from the peripheral blood (PB) of three patients in a typical fibrotic phase of the disease according to World Health Organization (WHO) criteria updated in 2016 (Arber et al, 2016)
In order to investigate the possible role of miR-382-5p in the pathogenesis of PMF, we performed a Gene expression profile (GEP) in CD34+ cells overexpressing miR-382-5p
Summary
Classical Philadelphia-negative chronic myeloproliferative neoplasms (MPNs) are clonal disorders of hematopoietic stem cell that include essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF; Vardiman et al, 2009) (Arber et al, 2016). The JAK/STAT signaling is a central downstream pathway for the majority of the inflammatory cytokines linked to MPNs and their progression (Vainchenker and Kralovics, 2017). PMF patients show increased serum level of pro-inflammatory cytokines (e.g., transforming growth factor-b1 (TGF-b1); interleukin (IL)-8, IL-12, IL-15), and excessive production of reactive oxygen species (ROS), which play a central role in the disease evolution (Bjorn and Hasselbalch, 2015; Tefferi et al, 2011; Vaidya et al, 2012). Marty et al demonstrated that the inhibition of ROS production could prevent the development of MPNs in JAK2V617F knock-in mouse model, giving further evidence of the significance of oxidative stress in the pathogenesis of these myeloid malignancies (Marty et al, 2013)
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