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Blood. 2016 Jun 30;127(26):3369-81. doi: 10.1182/blood-2015-09-668129. Epub 2016 Apr 13.

Runx1 downregulates stem cell and megakaryocytic transcription programs that support niche interactions.

Author information

1
Retroviral Pathogenesis, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany;
2
Retroviral Pathogenesis, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany; Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;
3
Institute of Biochemistry and Signal Transduction, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;
4
Retroviral Pathogenesis, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany; Biotechnology Institute, University of Ankara, Ankara, Turkey;
5
Virus Genomics, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany; Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;
6
Virus Genomics, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany;
7
Cancer and Haematology Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia; and Department of Medical Biology, The University of Melbourne, VIC, Australia.

Abstract

Disrupting mutations of the RUNX1 gene are found in 10% of patients with myelodysplasia (MDS) and 30% of patients with acute myeloid leukemia (AML). Previous studies have revealed an increase in hematopoietic stem cells (HSCs) and multipotent progenitor (MPP) cells in conditional Runx1-knockout (KO) mice, but the molecular mechanism is unresolved. We investigated the myeloid progenitor (MP) compartment in KO mice, arguing that disruptions at the HSC/MPP level may be amplified in downstream cells. We demonstrate that the MP compartment is increased by more than fivefold in Runx1 KO mice, with a prominent skewing toward megakaryocyte (Meg) progenitors. Runx1-deficient granulocyte-macrophage progenitors are characterized by increased cloning capacity, impaired development into mature cells, and HSC and Meg transcription signatures. An HSC/MPP subpopulation expressing Meg markers was also increased in Runx1-deficient mice. Rescue experiments coupled with transcriptome analysis and Runx1 DNA-binding assays demonstrated that granulocytic/monocytic (G/M) commitment is marked by Runx1 suppression of genes encoding adherence and motility proteins (Tek, Jam3, Plxnc1, Pcdh7, and Selp) that support HSC-Meg interactions with the BM niche. In vitro assays confirmed that enforced Tek expression in HSCs/MPPs increases Meg output. Interestingly, besides this key repressor function of Runx1 to control lineage decisions and cell numbers in progenitors, our study also revealed a critical activating function in erythroblast differentiation, in addition to its known importance in Meg and G/M maturation. Thus both repressor and activator functions of Runx1 at multiple hematopoietic stages and lineages likely contribute to the tumor suppressor activity in MDS and AML.

PMID:
27076172
DOI:
10.1182/blood-2015-09-668129
[Indexed for MEDLINE]
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