Transcriptional regulation of miR-10a/b by TWIST-1 in myelodysplastic syndromes

Abstract

The transcription factor TWIST-1 is up-regulated in CD34(+) cells in myelodysplastic syndrome and is involved in resistance to apoptosis. There is evidence that TWIST-1 affects apoptosis via microRNAs (miRs). Expression of miRs was determined in myeloid cell lines and primary CD34(+) marrow cells from patients with myelodysplastic syndrome and healthy donors using NanoString/array and validated by real-time-polymerase chain reaction. Expression levels of miR10a and miR10b were significantly higher in CD34(+) marrow cells from 28 patients with myelodysplastic syndrome than in CD34(+) cells from healthy donors (P=0.05 and P=0.012, respectively). Levels of miR10a/b correlated with TWIST-1 miR levels in CD34(+) myelodysplastic marrow cells (miR10a, R=+0.69, P<0.0001; miR10b, R=+0.56, P=0.0008). Inhibition of miR10a/10b in clonal cells interfered with proliferation and enhanced sensitivity to apoptosis, which involved NF-κB-dependent p53 activation. These data support a role for miR10a/10b in the regulation of apoptosis in myelodysplastic syndrome and suggest the TWIST-1/miR10a/b-axis as a therapeutic target in myelodysplastic syndrome.