title: Low DICER1 expression is associated with attenuated neutrophil differentiation and autophagy of NB4 APL cells.
abstract: Successful myeloid differentiation depends on the expression of a series of miRNAs. Thus, it is hardly surprising that miRNAs are globally repressed in AML, a disease mainly characterized by a block in cellular myeloid differentiation. Studies investigating the mechanisms for low miRNA expression in AML has mostly focused on altered transcriptional regulation or deletions, whereas defective miRNA processing has received less attention. In this study, we report that the expression of the key miRNA processing enzyme DICER1 is down-regulated in primary AML patient samples and healthy CD34(+) progenitor cells as compared with granulocytes. In line with these findings, Dicer1 expression was induced significantly in AML cell lines upon neutrophil differentiation. The knocking down of DICER1 in AML cells significantly attenuated neutrophil differentiation, which was paralleled by decreased expression of miRNAs involved in this process. Moreover, we found that inhibiting DICER1 attenuated the activation of autophagy, a cellular recycling process that is needed for proper neutrophil differentiation of AML cells. Our results clearly indicate that DICER1 plays a novel role in neutrophil differentiation as well as in myeloid autophagy of AML cells.
authors.affiliation: *Division of Experimental Pathology, Institute of Pathology, and Graduate School for Cellular and Biomedical Sciences, University of Bern, Switzerland; Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, USA; and Department of Medical Oncology, Inselspital, Bern University Hospital, Bern, Switzerland.
authors.forename: Julian
authors.initials: J
authors.lastname: Wampfler
authors.affiliation: *Division of Experimental Pathology, Institute of Pathology, and Graduate School for Cellular and Biomedical Sciences, University of Bern, Switzerland; Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, USA; and Department of Medical Oncology, Inselspital, Bern University Hospital, Bern, Switzerland.
authors.forename: Elena A
authors.initials: EA
authors.lastname: Federzoni
authors.affiliation: *Division of Experimental Pathology, Institute of Pathology, and Graduate School for Cellular and Biomedical Sciences, University of Bern, Switzerland; Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, USA; and Department of Medical Oncology, Inselspital, Bern University Hospital, Bern, Switzerland.
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Torbett
authors.affiliation: *Division of Experimental Pathology, Institute of Pathology, and Graduate School for Cellular and Biomedical Sciences, University of Bern, Switzerland; Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, USA; and Department of Medical Oncology, Inselspital, Bern University Hospital, Bern, Switzerland.
authors.forename: Martin F
authors.initials: MF
authors.lastname: Fey
authors.affiliation: *Division of Experimental Pathology, Institute of Pathology, and Graduate School for Cellular and Biomedical Sciences, University of Bern, Switzerland; Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, USA; and Department of Medical Oncology, Inselspital, Bern University Hospital, Bern, Switzerland mario.tschan@pathology.unibe.ch.
authors.forename: Mario P
authors.initials: MP
authors.lastname: Tschan
mesh_terms: D001343:Autophagy / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D053487:DEAD-box RNA Helicases / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000378:metabolism / Q000473:pathology; D035683:MicroRNAs / Q000378:metabolism; D009504:Neutrophils / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D012323:RNA Processing, Post-Transcriptional / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D043244:Ribonuclease III / Q000378:metabolism*; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D035683:MicroRNAs; D012333:RNA, Messenger; D014212:Tretinoin; C408087:DICER1 protein, human; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases
keywords: AML; RNAi; processing machinery