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Acute Leukemias

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

Leukemia volume 29, pages 535–547 (2015)Cite this article

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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.

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Acknowledgements

We thank Professor Dr M Mallardo for providing miR-155 promoter luciferase constructs, Professor Dr T Kitamura for STAT5 and STAT5 1*6 expression constructs and Professor Dr T Fischer for providing FLT3-WT, FLT3-ITD and FLT3-TKD expression constructs. This study was supported by grants from DFG (German Research Foundation, BE 2042/7-1), Deutsche José Carreras Leukämie-Stiftung e.V. (DJCLS R 11/17), Deutsche Krebshilfe and Translational Centre for Regenerative Medicine Leipzig (to GB), Deutsche José Carreras Leukämie-Stiftung e.V. (DJCLS F 08/05) (to DG), Deutsche José Carreras Leukämie-Stiftung e.V. (DJCLS F 12/03) (to AAW) and the National Institute of Health (CA118316) (to DGT).

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Authors and Affiliations

  1. Division of Hematology and Oncology, Leipzig University Hospital, Leipzig, Germany

    D Gerloff, A A Wurm, D Bräuer-Hartmann, C Katzerke, J-U Hartmann, D Niederwieser & G Behre

  2. Department of Internal Medicine III, Technical University Munich, Munich, Germany

    R Grundler

  3. Cancer Science Institute, National University of Singapore, Singapore

    V Madan & D G Tenen

  4. Department of Medicine IV, Hematology and Oncology, University of Halle, Halle, Germany

    C Müller-Tidow

  5. Department of Hematology/Oncology 1, University Medical Center Freiburg, Freiburg, Germany

    J Duyster

  6. Harvard Stem Cell Institute, Harvard Medical School, Boston, MA, USA

    D G Tenen

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Gerloff, D., Grundler, R., Wurm, A. et al. NF-κB/STAT5/miR-155 network targets PU.1 in FLT3-ITD-driven acute myeloid leukemia. Leukemia 29, 535–547 (2015). https://doi.org/10.1038/leu.2014.231

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