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

D Gerloff; R Grundler; A A Wurm; D Bräuer-Hartmann; C Katzerke; J-U Hartmann; V Madan; C Müller-Tidow; J Duyster; D G Tenen; D Niederwieser; G Behre

doi:10.1038/leu.2014.231

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

Leukemia. 2015 Mar;29(3):535-47. doi: 10.1038/leu.2014.231. Epub 2014 Aug 5.

Authors

D Gerloff¹, R Grundler², A A Wurm¹, D Bräuer-Hartmann¹, C Katzerke¹, J-U Hartmann¹, V Madan³, C Müller-Tidow⁴, J Duyster⁵, D G Tenen⁶, D Niederwieser¹, G Behre¹

Affiliations

¹ Division of Hematology and Oncology, Leipzig University Hospital, Leipzig, Germany.
² Department of Internal Medicine III, Technical University Munich, Munich, Germany.
³ Cancer Science Institute, National University of Singapore, Singapore.
⁴ Department of Medicine IV, Hematology and Oncology, University of Halle, Halle, Germany.
⁵ Department of Hematology/Oncology 1, University Medical Center Freiburg, Freiburg, Germany.
⁶ 1] Cancer Science Institute, National University of Singapore, Singapore [2] Harvard Stem Cell Institute, Harvard Medical School, Boston, MA, USA.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Aged
Animals
Female
Gene Expression Regulation, Leukemic*
Humans
Leukemia, Myeloid, Acute / genetics*
Leukemia, Myeloid, Acute / metabolism
Leukemia, Myeloid, Acute / pathology
Male
Mice
Mice, Transgenic
MicroRNAs / antagonists & inhibitors
MicroRNAs / genetics*
MicroRNAs / metabolism
Middle Aged
Mutation
Myeloid Cells / metabolism
Myeloid Cells / pathology
Proto-Oncogene Proteins / genetics*
Proto-Oncogene Proteins / metabolism
RNA, Small Interfering / genetics
RNA, Small Interfering / metabolism
STAT5 Transcription Factor / genetics*
STAT5 Transcription Factor / metabolism
Signal Transduction
Trans-Activators / genetics*
Trans-Activators / metabolism
Transcription Factor RelA / genetics*
Transcription Factor RelA / metabolism
fms-Like Tyrosine Kinase 3 / genetics*
fms-Like Tyrosine Kinase 3 / metabolism

Substances

MIRN155 microRNA, human
MicroRNAs
Proto-Oncogene Proteins
RNA, Small Interfering
STAT5 Transcription Factor
Trans-Activators
Transcription Factor RelA
proto-oncogene protein Spi-1
FLT3 protein, human
fms-Like Tyrosine Kinase 3

Abstract

Publication types

MeSH terms

Substances

Grants and funding