Runx1 downregulates stem cell and megakaryocytic transcription programs that support niche interactions
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Runx1 downregulates stem cell and megakaryocytic transcription programs that support niche interactions. / Behrens, Kira; Triviai, Ioanna; Schwieger, Maike; Tekin, Nilgün; Alawi, Malik; Spohn, Michael; Indenbirken, Daniela; Ziegler, Marion; Müller, Ursula; Alexander, Warren S; Stocking, Carol.
In: BLOOD, Vol. 127, No. 26, 30.06.2016, p. 3369-81.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Runx1 downregulates stem cell and megakaryocytic transcription programs that support niche interactions
AU - Behrens, Kira
AU - Triviai, Ioanna
AU - Schwieger, Maike
AU - Tekin, Nilgün
AU - Alawi, Malik
AU - Spohn, Michael
AU - Indenbirken, Daniela
AU - Ziegler, Marion
AU - Müller, Ursula
AU - Alexander, Warren S
AU - Stocking, Carol
N1 - © 2016 by The American Society of Hematology.
PY - 2016/6/30
Y1 - 2016/6/30
N2 - 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.
AB - 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.
KW - Animals
KW - Core Binding Factor Alpha 2 Subunit
KW - Gene Expression Regulation
KW - Hematopoietic Stem Cells
KW - Humans
KW - Leukemia, Myeloid, Acute
KW - Megakaryocytes
KW - Mice
KW - Mice, Knockout
KW - Myelodysplastic Syndromes
KW - Transcription, Genetic
KW - Tumor Suppressor Proteins
KW - Journal Article
U2 - 10.1182/blood-2015-09-668129
DO - 10.1182/blood-2015-09-668129
M3 - SCORING: Journal article
C2 - 27076172
VL - 127
SP - 3369
EP - 3381
JO - BLOOD
JF - BLOOD
SN - 0006-4971
IS - 26
ER -