title: NF-κB/STAT5/miR-155 network targets PU.1 in FLT3-ITD-driven acute myeloid leukemia.
abstract: Almost 30% of all acute myeloid leukemias (AML) are associated with an internal tandem duplication (ITD) in the juxtamembrane domain of FMS-like tyrosine kinase 3 receptor (FLT3). Patients with FLT3-ITD mutations tend to have a poor prognosis. MicroRNAs (miRNAs) have a pivotal role in myeloid differentiation and leukemia. MiRNA-155 (MiR-155) was found to be upregulated in FLT3-ITD-associated AMLs. In this study, we discovered that FLT3-ITD signaling induces the oncogenic miR-155. We show in vitro and in vivo that miR-155 expression is regulated by FLT3-ITD downstream targets nuclear factor-κB (p65) and signal transducer and activator of transcription 5 (STAT5). Further, we demonstrate that miR-155 targets the myeloid transcription factor PU.1. Knockdown of miR-155 or overexpression of PU.1 blocks proliferation and induces apoptosis of FLT3-ITD-associated leukemic cells. Our data demonstrate a novel network in which FLT3-ITD signaling induces oncogenic miR-155 by p65 and STAT5 in AML, thereby targeting transcription factor PU.1.
authors.affiliation: Division of Hematology and Oncology, Leipzig University Hospital, Leipzig, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Gerloff
authors.affiliation: Department of Internal Medicine III, Technical University Munich, Munich, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Grundler
authors.affiliation: Division of Hematology and Oncology, Leipzig University Hospital, Leipzig, Germany.
authors.forename: A A
authors.initials: AA
authors.lastname: Wurm
authors.affiliation: Division of Hematology and Oncology, Leipzig University Hospital, Leipzig, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Bräuer-Hartmann
authors.affiliation: Division of Hematology and Oncology, Leipzig University Hospital, Leipzig, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Katzerke
authors.affiliation: Division of Hematology and Oncology, Leipzig University Hospital, Leipzig, Germany.
authors.forename: J-U
authors.initials: JU
authors.lastname: Hartmann
authors.affiliation: Cancer Science Institute, National University of Singapore, Singapore.
authors.forename: V
authors.initials: V
authors.lastname: Madan
authors.affiliation: Department of Medicine IV, Hematology and Oncology, University of Halle, Halle, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Müller-Tidow
authors.affiliation: Department of Hematology/Oncology 1, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Duyster
authors.affiliation: 1] Cancer Science Institute, National University of Singapore, Singapore [2] Harvard Stem Cell Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: D G
authors.initials: DG
authors.lastname: Tenen
authors.affiliation: Division of Hematology and Oncology, Leipzig University Hospital, Leipzig, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Niederwieser
authors.affiliation: Division of Hematology and Oncology, Leipzig University Hospital, Leipzig, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Behre
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009154:Mutation; D022423:Myeloid Cells / Q000378:metabolism / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D051996:Transcription Factor RelA / Q000235:genetics* / Q000378:metabolism; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics* / Q000378:metabolism; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D035683:MicroRNAs; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D051996:Transcription Factor RelA; D051941:fms-Like Tyrosine Kinase 3; D000099232:Proto-Oncogene Protein Spi-1; C524942:MIRN155 microRNA, human; C497970:FLT3 protein, human
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