MicroRNAs 17-5p–20a–106a control monocytopoiesis through AML1 targeting and M-CSF receptor upregulation

Abstract

We investigated the role of microRNAs (miRNA) 17-5p, 20a and 106a in monocytic differentiation and maturation. In unilineage monocytic culture generated by haematopoietic progenitor cells these miRNAs are downregulated, whereas the transcription factor acute myeloid leukaemia-1 (AML1; also known as Runt-related transcription factor 1, Runx1) is upregulated at protein but not mRNA level. As miRNAs 17-5p, 20a and 106a bind the AML1 mRNA 3'UTR, their decline may unblock AML1 translation. Accordingly, transfection with miRNA 17-5p-20a-106a suppresses AML1 protein expression, leading to M-CSF receptor (M-CSFR) downregulation, enhanced blast proliferation and inhibition of monocytic differentiation and maturation. Treatment with anti-miRNA 17-5p, 20a and 106a causes opposite effects. Knockdown of AML1 or M-CSFR by short interfering RNA (siRNA) mimics the action of the miRNA 17-5p-20a-106a, confirming that these miRNAs target AML1, which promotes M-CSFR transcription. In addition, AML1 binds the miRNA 17-5p-92 and 106a-92 cluster promoters and transcriptionally inhibits the expression of miRNA 17-5p-20a-106a. These studies indicate that monocytopoiesis is controlled by a circuitry involving sequentially miRNA 17-5p-20a-106a, AML1 and M-CSFR, whereby miRNA 17-5p-20a-106a function as a master gene complex interlinked with AML1 in a mutual negative feedback loop.

Megakaryocytic expression of miRNA 10a, 17-5p, 20a and 126 in Philadelphia chromosome-negative myeloproliferative neoplasm

“…As reported [15], RUNX1 protein was localised in the nucleus, predominantly in megakaryocytes but also in erythropoiesis (Fig. 2 e and f).…”

“…A potential target of the miRNA 17-5p-92 cluster and miRNA 126 is the Runt-related transcription factor 1 (RUNX1, also designated acute myeloid leukemia 1, AML1) [11] which is one of the central transcription factors in normal and leukaemic megakaryopoiesis [13,14]. In monocytic differentiation, it has been shown that RUNX1 is inhibited by the miRNA 17-5p-92 cluster and in a negative feed-back regulation mechanism RUNX1 protein binds to the promoter of miRNA 17-5p-92 cluster genes [15].…”

MicroRNA‐124a is a key regulator of proliferation and monocyte chemoattractant protein 1 secretion in fibroblast‐like synoviocytes from patients with rheumatoid arthritis

“…Moreover, several miRNA have been shown to regulate the 3Ј-UTR of mRNA that encode transcription factors (49), and a circuit that sequentially involves miRNA and transcription factors in a mutual negative feedback loop has been described (48,49). As for the transcription factors, it has been reported that REST inhibits miR124a expression in non-neuronal cells.…”

MicroRNA-155 Regulates Inflammatory Cytokine Production in Tumor-associated Macrophages via Targeting C/EBPβ

“…Mammalian miRNAs have emerged as the key post-transcriptional regulators of gene expression in various biological processes, including those linked to cancer and immunity (19)(20)(21)38). The present study provides evidence that miR-155 regulates inflammatory cytokine production via C/EBP targeting.…”