title: PML/RARα-Regulated miR-181a/b Cluster Targets the Tumor Suppressor RASSF1A in Acute Promyelocytic Leukemia.
abstract: In acute promyelocytic leukemia (APL), all-trans retinoic acid (ATRA) treatment induces granulocytic maturation and complete remission of leukemia. microRNAs are known to be critical players in the formation of the leukemic phenotype. In this study, we report downregulation of the miR-181a/b gene cluster in APL blasts and NB4 leukemia cells upon ATRA treatment as a key event in the drug response. We found that miR-181a/b expression was activated by the PML/RARα oncogene in cells and transgenic knock-in mice, an observation confirmed and extended by evidence of enhanced expression of miR-181a/b in APL patient specimens. RNA interference (RNAi)-mediated attenuation of miR-181a/b expression in NB4 cells was sufficient to reduce colony-forming capacity, proliferation, and survival. Mechanistic investigations revealed that miR-181a/b targets the ATRA-regulated tumor suppressor gene RASSF1A by direct binding to its 3'-untranslated region. Enforced expression of miR-181a/b or RNAi-mediated attenuation of RASSF1A inhibited ATRA-induced granulocytic differentiation via regulation of the cell-cycle regulator cyclin D1. Conversely, RASSF1A overexpression enhanced apoptosis. Finally, RASSF1A levels were reduced in PML/RARα knock-in mice and APL patient samples. Taken together, our results define miR-181a and miR-181b as oncomiRs in PML/RARα-associated APL, and they reveal RASSF1A as a pivotal element in the granulocytic differentiation program induced by ATRA in APL.
authors.affiliation: Division of Hematology and Oncology, Leipzig University Hospital, Leipzig, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Bräuer-Hartmann
authors.affiliation: Division of Hematology and Oncology, Leipzig University Hospital, Leipzig, Germany.
authors.forename: Jens-Uwe
authors.initials: JU
authors.lastname: Hartmann
authors.affiliation: Division of Hematology and Oncology, Leipzig University Hospital, Leipzig, Germany.
authors.forename: Alexander Arthur
authors.initials: AA
authors.lastname: Wurm
authors.affiliation: Division of Hematology and Oncology, Leipzig University Hospital, Leipzig, Germany.
authors.forename: Dennis
authors.initials: D
authors.lastname: Gerloff
authors.affiliation: Division of Hematology and Oncology, Leipzig University Hospital, Leipzig, Germany.
authors.forename: Christiane
authors.initials: C
authors.lastname: Katzerke
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Maria Vittoria
authors.initials: MV
authors.lastname: Verga Falzacappa
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Pier Giuseppe
authors.initials: PG
authors.lastname: Pelicci
authors.affiliation: Department of Internal Medicine IV, Hematology/Oncology, University Hospital Halle, Halle, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Müller-Tidow
authors.affiliation: Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts. Cancer Science Institute, National University of Singapore, Singapore.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Tenen
authors.affiliation: Division of Hematology and Oncology, Leipzig University Hospital, Leipzig, Germany.
authors.forename: Dietger
authors.initials: D
authors.lastname: Niederwieser
authors.affiliation: Division of Hematology and Oncology, Leipzig University Hospital, Leipzig, Germany. gerhard.behre@medizin.uni-leipzig.de.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Behre
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D005434:Flow Cytometry; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D057809:HEK293 Cells; D018922:HL-60 Cells; D006801:Humans; D015151:Immunoblotting; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics*; D005810:Multigene Family; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D000071156:Promyelocytic Leukemia Protein; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D020298:U937 Cells
chemical_list: D000970:Antineoplastic Agents; C540193:MIrn181 microRNA, human; D035683:MicroRNAs; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D000071156:Promyelocytic Leukemia Protein; C000607071:RARA protein, human; C411762:RASSF1 protein, human; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; C070576:PML protein, human; D014212:Tretinoin