MicroRNAs 17-5p-20a-106a control monocytopoiesis through AML1 targeting and M-CSF receptor upregulation.
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.
Fontana
Laura
L
Department of Haematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy. lfontana@iss.it
Pelosi
Elvira
E
Greco
Paolo
P
Racanicchi
Serena
S
Testa
Ugo
U
Liuzzi
Francesca
F
Croce
Carlo M
CM
Brunetti
Ercole
E
Grignani
Francesco
F
Peschle
Cesare
C
D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D050676:Core Binding Factor Alpha 2 Subunit / Q000378:metabolism*; D025461:Feedback, Physiological; D005260:Female; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000502:physiology; D006801:Humans; D035683:MicroRNAs / Q000502:physiology*; D009000:Monocytes / Q000166:cytology* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000378:metabolism; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000096:biosynthesis*; D015854:Up-Regulation
D050676:Core Binding Factor Alpha 2 Subunit; D035683:MicroRNAs; D034741:RNA, Small Interfering; C493728:RUNX1 protein, human; D016186:Receptor, Macrophage Colony-Stimulating Factor