NF-κB/STAT5/miR-155 network targets PU.1 in FLT3-ITD-driven acute myeloid leukemia

• Published in: Leukemia Vol. 29; no. 3; pp. 535 - 547
• Main Authors: Gerloff, D, Grundler, R, Wurm, A A, Bräuer-Hartmann, D, Katzerke, C, Hartmann, J-U, Madan, V, Müller-Tidow, C, Duyster, J, Tenen, D G, Niederwieser, D, Behre, G
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-03-2015; Nature Publishing Group
• Subjects: 13; 13/100; 13/31; 38/109; 631/337/384/331; 631/45/612/822; 631/67/1990/283; 631/80/86; 692/699/67/1990/283/1897; Acute myeloid leukemia; Adolescent; Adult; Aged; Animals; Apoptosis; Cancer Research; Cell proliferation; Cell receptors; Critical Care Medicine; Female; Flt3 protein; fms-Like Tyrosine Kinase 3 - genetics; fms-Like Tyrosine Kinase 3 - metabolism; Gene Expression Regulation, Leukemic; Health aspects; Hematology; Humans; Intensive; Internal Medicine; Kinases; Leukemia; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - metabolism; Leukemia, Myeloid, Acute - pathology; Male; Medicine; Medicine & Public Health; Mice; Mice, Transgenic; MicroRNAs; MicroRNAs - antagonists & inhibitors; MicroRNAs - genetics; MicroRNAs - metabolism; Middle Aged; miRNA; Mutation; Myeloid Cells - metabolism; Myeloid Cells - pathology; Myeloid leukemia; NF-κB protein; Oncology; original-article; Properties; Protein-tyrosine kinase; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; PU.1 protein; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; Signal Transduction; Signaling; Stat5 protein; STAT5 Transcription Factor - genetics; STAT5 Transcription Factor - metabolism; Trans-Activators - genetics; Trans-Activators - metabolism; Transcription Factor RelA - genetics; Transcription Factor RelA - metabolism; Transcription factors; Tyrosine
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2014.231

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.