Runx1 downregulates stem cell/megakaryocytic transcription programs that support niche interactions
Details
Publication Year 2016-04-13, Volume 127, Issue #26, Page 3369-3381
Journal Title
Blood
Publication Type
Journal Article
Abstract
Disrupting mutations of theRUNX1gene are found in 10% of Myelodysplasia (MDS) and 30% of Acute Myeloid Leukemia (AML) patients. Previous studies have revealed an increase in hematopoietic stem and multipotent progenitor cells (HSC/MPP) in conditionalRunx1knockout (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 >5-fold inRunx1KO mice, with a prominent skewing towards Megakaryocyte (Meg) progenitors. Runx1-deficient Granulocyte-Macrophage Progenitors (GMPs) are characterized by increased cloning capacity, impaired development into mature cells, and HSC and Meg transcription signatures. A 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 lineage separation between Meg and GM 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 vitroassays confirmed that enforced Tek expression in HSC/MPP 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.
Publisher
AHS
WEHI Research Division(s)
Cancer And Haematology
PubMed ID
27076172
Rights Notice
Refer to copyright notice on published article.


Creation Date: 2016-04-28 02:07:00
Last Modified: 2018-07-09 03:14:41
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