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Cited by 135Acute Myeloid Leukemia ResearchMicroRNA in disease regulationRetinoids in leukemia and cellular processes

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

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Gerloff, D, Grundler, R, Wurm, A A, Bräuer-Hartmann, D, Katzerke, C, Hartmann, J-U, Madan, V, Müller-Tidow, C +4 more·2015·Leukemia
DOI 10.1038/leu.2014.231PMC PMC4490787
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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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  • A wide array of myeloid leukemia-associated oncogenic lesions can interfere with PU.1 expression or function, including PML/RARA, AML1-ETO, NPM1c, CEBPA, and mitogenic kinase mutations in BCR/ABL and Flt3ITD.

    “a wide array of myeloid leukemia–associated oncogenic lesions can interfere with PU.1 expression or function, including PML/RARA, AML1-ETO, NPM1c, CEBPA, and mitogenic kinase mutations in BCR/ABL and Flt3ITD (Gerloff et al., 2015; McKenzie et al., 2019; Mueller et al., 2006; Noguera et al., 2016; Vangala et al., 2003; Yang et al., 2012).”

    From PU.1 enforces quiescence and limits hematopoietic stem cell expansion during inflammatory stress (2021) · cites this paper as Gerloff et al., 2015

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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.
Affiliations
  • University Hospital Leipzig (DE)
  • Technical University of Munich (DE)
  • National University of Singapore (SG)
  • University Medical Center Freiburg (DE)
  • Harvard University (US)
Corresponding author
Behre, G
ORCID
Venue
Leukemia
Publisher
Springer Science and Business Media LLC
Published
2014-08-05
Volume
29
Issue
3
Pages
535-547
ISSN
  • 0887-6924 (ISSN-L)
  • 1476-5551
DOI
10.1038/leu.2014.231
PMC
PMC4490787
OpenAlex
W1972428122
Cited by
135
References
4
Citations by year
2026: 4 · 2025: 7 · 2024: 6 · 2023: 14 · 2022: 13 · 2021: 11 · 2020: 7 · 2019: 18 · 2018: 19 · 2017: 13 · 2016: 18 · 2015: 4
FWCI
8.27
Type
journal article
Language
en
Open access
Licence
Locations
  • Leukemia (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • FreiDok plus (Universitätsbibliothek Freiburg) (submittedVersion)
Funders
  • National Heart, Lung, and Blood Institute (R01HL112719)
  • National Cancer Institute (R01CA118316, CA118316, P01CA066996)
Topics
  • Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
Keywords
acute myeloid leukemia, FLT3-ITD, miR-155, PU.1, NF-κB p65, STAT5, microRNA regulation, transcriptional regulation, leukemia cell proliferation, apoptosis, myeloid differentiation
MeSH terms
Proto-Oncogene Protein Spi-1, Adolescent, Adult, Aged, Animals, Female, Humans, Male, Mice, Transgenic, Middle Aged, Mutation, Proto-Oncogene Proteins, Signal Transduction, Leukemia, Myeloid, Acute, Trans-Activators, Gene Expression Regulation, Leukemic, Myeloid Cells, RNA, Small Interfering, MicroRNAs, STAT5 Transcription Factor, Mice, fms-Like Tyrosine Kinase 3, Transcription Factor RelA

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