Abstract
Myelodysplastic syndromes (MDS) are characterized by impaired proliferation and differentiation of hematopoietic stem cells. The participation of toll-like receptor (TLR)-mediated signaling in MDS is well documented. Increased TLR signaling leads to the constitutive activation of NF-κB, which mediates inflammation, cell proliferation and apoptosis. In addition, the TLR pathway induces the expression of miRNAs which participate in the fine-tuning of the inflammatory response. miRNAs also regulate other biological processes, including hematopoiesis. miR-125a and miR-125b are known modulators of hematopoiesis and are abnormally expressed in several hematologic malignancies. However, little is known about their role in MDS. NF-κB-activating ability has been described for both miRNAs. We studied the role of miR-125a/miR-125b in MDS and their relationship with TLR signaling and hematopoietic differentiation. Our results indicate that miR-125a is significantly overexpressed in MDS patients and correlates negatively with patient survival. Expression of miR-99b, which is clustered with miR-125a, is also directly correlated with prognosis of MDS. Both miR-125a and miR-99b activated NF-κB in vitro; however, we observed a negative correlation between miR-99b expression and the levels of TLR2, TLR7 and two downstream genes, suggesting that NF-κB activation by the miRNA cluster occurs in the absence of TLR signaling. We also show that TLR7 is negatively correlated with patient survival in MDS. In addition, our data suggest that miR-125a may act as an NF-κB inhibitor upon TLR stimulation. These results indicate that miR-125a is involved in the fine-tuning of NF-κB activity and that its effects may depend on the status of the TLR pathway. Furthermore, we observed that miR-125a inhibits erythroid differentiation in leukemia and MDS cell lines. Therefore, this miRNA could serve as a prognostic marker and a potential therapeutic target in MDS.
Highlights
Myelodysplastic syndromes (MDS) are a heterogenous group of clonal hematologic malignancies associated with hematopoietic stem cell dysfunctions which lead to impaired cell proliferation and differentiation [1]
In order to find out if miR-125a and/or miR-125b play a relevant role in the pathogenesis of MDS, their relative expression in CD34+ cells from bone marrow (BM) of MDS patients was analyzed by Quantitative real-time PCR (qPCR) and compared to their expression in BM CD34+ cells from healthy donors
Provided that miR-125a and miR-125b are potential NF-kB regulators [43] and in light of the results presented above, we studied the associations between miR-125b or the miR-99b/let7e/miR-125a cluster and the expression of TLR2, myeloid differentiation primary response gene 88 (MyD88) and the histone demethylase JMJD3, which we had identified as a positive regulator of inflammation downstream of NF-kB, that could participate in a positive feedback loop resulting in the hyperactivation of this factor [14]
Summary
Myelodysplastic syndromes (MDS) are a heterogenous group of clonal hematologic malignancies associated with hematopoietic stem cell dysfunctions which lead to impaired cell proliferation and differentiation [1]. TLRs signal through adaptor molecules like the myeloid differentiation primary response gene 88 (MyD88), inducing the transcription of interferons and proinflammatory cytokines through the activation of transcription factors like NF-kB. The presence of TLRs in BM stem and progenitor cells (CD34+) and their involvement in the modulation of myeloid differentiation has been extensively reported [7,9,10] and there is compelling evidence that TLR signaling is important in the pathogenesis of MDS (reviewed in [8]). TLR1, TLR2, TLR4 and TLR9 have been found to be overexpressed in PLOS ONE | www.plosone.org miR-125a Is Overexpressed in MDS
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