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Acute erythroid leukemia (AEL) is characterized by lower incidence, poorer prognosis and worse survival than other types of leukemia and results from collaboration of malignant proliferation and erythroid differentiation blockage. The expression, function and therapeutic significance of noncoding RNAs in AEL have not been well studied. Here, we show that one miRNA cluster, including miR-23a, -27a and -24, is dramatically downregulated in AEL patients. Restoration of miR-23a, -27a and -24 expression induces apoptosis and erythropoiesis, inhibits adverse growth and partly relieves the leukemic symptoms of AEL patients. At the whole-genome scale, we identify that miR-23a, -27a and -24 synergistically target multiple members of the oncogenic gp130-JAK1-Stat3 pathway, and thus reinforce their inhibition on the cascade to regulate cell proliferation and apoptosis. Importantly, Ruxolitinib, a JAK1 inhibitor, could rescue the phenotypic changes induced by miR-23a, -27a and -24 inhibitors. Furthermore, miR-23a cluster-mediated-inactivation of the JAK1-Stat3 pathway promotes the expression and activity of GATA1 via inhibiting PU.1, thereby improving erythroid differentiation. Collectively, we reveal an important regulatory circuit comprising GATA1, the miR-23a cluster and gp130-JAK1-Stat3 pathway, that synergistically facilitates apoptosis and erythropoiesis and restrains adverse proliferation, indicating the therapeutic significance of miR-23a, -27a and -24 for AEL treatment.
The expression of glucocorticoid receptor (GR) isoforms has been linked to glucocorticoid (GC) resistance in various diseases treated with GC. However, existing data are conflicting in these diseases, and little information is available regarding immune thrombocytopenia (ITP). To further investigate the role of GR isoforms in GC resistance in adult ITP patients, we measured the mRNA expression of GR isoforms (GRα, GRβ, GRγ, GRp) in peripheral blood mononuclear cells (PBMC) from 54 newly diagnosed ITP patients, including GC-sensitive (GCS) and GC-resistant (GCR) patients and 35 healthy volunteers. The GRα and GRβ proteins in PBMC, nuclear factor-κB (NF-κB), and activator protein-1 (AP-1) in the nucleus were detected by Western blotting. Compared to normal subjects, both GRα and GRβ mRNAs were significantly increased in ITP patients (p < 0.05), while there was no significant difference in the mRNA expression of GRγ and GRp. Compared to GCR patients, the expressions of GRα mRNA and GRα protein were significantly higher in GCS patients (p < 0.05). Moreover, no significant difference in the mRNA expression of the GRβ, GRγ, and GRp isoforms was observed between GCS and GCR patients and the GRβ protein could not be detected. Compared to GCS group, the expression of p65/NF-κB was significantly higher in the GCR group (p < 0.05). Overall, we did not find differences in c-Jun/AP-1 protein expression between GCS and GCR patients. In summary, GC resistance in adult ITP patients is associated with a reduced expression of GRα, which may be related with increased NF-κB. GRβ was very low and may not be involved in GC resistance in adult ITP, warranting further exploration.