miR-181c regulates MCL1 and cell survival in GATA2 deficient cells

Abstract

GATA2 is a transcription factor critical for hematopoiesis. Germline mutations in GATA binding protein 2 (GATA2) led to haploinsufficiency, severe cytopenias of multiple cell lineages, susceptibility to infections and strong propensity to develop myelodysplastic syndrome, and acute myeloid leukemia. Mechanisms of progressive cytopenias remain unclear. MicroRNA (miRNA) represents a unique mechanism of post-transcriptional gene regulation. In this study, miRNA profiles were evaluated and eight miRNAs were found to be differentially expressed (≥2-fold, P ≤ 0.05) in patient-derived cell lines (N = 13) in comparison to controls (N = 10). miR-9, miR-181a-2-3p, miR-181c, miR-181c-3p, miR-486-3p, and miR-582 showed increased expression, whereas miR-223 and miR-424-3p showed decreased expression. Cell death assays indicated that miR-181c potently induces cell death in lymphoid (Ly-8 and SP-53) and myeloid (HL-60) cell lines. miR-181c was predicted to target myeloid cell leukemia (MCL)1, which was confirmed by transfection assays, resulting in significantly reduced MCL1 mRNA and decreased live cell numbers. Bone marrow analysis of 34 GATA2 patients showed significantly decreased cellularity, CD34-positive cells, monocytes, dendritic cells, NK cells, B cells, and B cell precursors in comparison to healthy controls (N = 29; P < 0.001 for each), which was accompanied by decreased levels of MCL1 (P < 0.05). GATA2 expression led to significant repression of miR-181c expression in transfection experiments. Conversely, knockdown of GATA2 led to increased miR-181c expression. These findings indicate that miR-181c expression is increased and MCL1 levels decreased in GATA2 deficiency cells, and that GATA2 represses miR-181c transcription. Increased miR-181c may contribute to elevated cell death and cytopenia in GATA2 deficiency potentially through down-regulation of MCL1.

Global miRNA profiling reveals key molecules that contribute to different chronic lymphocytic leukemia incidences in Asian and Western populations

“…Consistently, analysis of two publicly available datasets GSE108901 and GSE66186, which contained miRNA expression data mainly from Western CLL patients and Western normal individuals, also showed higher expression of pro-CLL miR-4485 and lower expression of the CLL-suppressive miRNA in CLL patients compared with healthy individuals (Online Supplementary Figure S4). Since the five miRNA identified in Figure 2B (miR-181d, miR-181c, miR-363, miR-138, and miR-181a) with putative anti-CLL function had been reported previously, 23,[28][29][30][31][32][33][34] whereas miR-4485 was the only microRNA identified as a putative CLL-promoting molecule with high expression in CLL cells in both ethnic groups and a downregulation in Asian normal B lymphocytes, we thus focused our efforts on investigating the role of miR-4485. In order to investigate the functional impact of miR-4485 on CLL cells, we first used a lentiviral There was a significant decrease in cell proliferation after MEC1 or MEC2 cells were transfected to express miR-4485 antagonist, whereas transfection using the control vector did not affect cell proliferat6ion (Figure 3B).…”

Exosomal‐miR‐522‐3p derived from cancer‐associated fibroblasts accelerates tumor metastasis and angiogenesis via repression bone morphogenetic protein 5 in colorectal cancer

“…miRNAs have been confirmed to modulate mRNA expression by inhibiting mRNA translation 18,19 . Previous reports have shown that miRNAs are able to play as a critical modulator in the progression of CRC.…”

“…miRNAs have been confirmed to modulate mRNA expression by inhibiting mRNA translation. 18,19 Previous reports have shown that miRNAs are able to play as a critical modulator in the progression of CRC. Wang et al revealed that miR-22-3p suppressed the growth of CRC cells through downregulation of PI3K/Akt signaling.…”