title: Runx1 downregulates stem cell and megakaryocytic transcription programs that support niche interactions.
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.
authors.affiliation: Retroviral Pathogenesis, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany;
authors.forename: Kira
authors.initials: K
authors.lastname: Behrens
authors.affiliation: Retroviral Pathogenesis, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany; Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;
authors.forename: Ioanna
authors.initials: I
authors.lastname: Triviai
authors.affiliation: Institute of Biochemistry and Signal Transduction, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;
authors.forename: Maike
authors.initials: M
authors.lastname: Schwieger
authors.affiliation: Retroviral Pathogenesis, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany; Biotechnology Institute, University of Ankara, Ankara, Turkey;
authors.forename: Nilgün
authors.initials: N
authors.lastname: Tekin
authors.affiliation: Virus Genomics, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany; Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;
authors.forename: Malik
authors.initials: M
authors.lastname: Alawi
authors.affiliation: Virus Genomics, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany;
authors.forename: Michael
authors.initials: M
authors.lastname: Spohn
authors.affiliation: Virus Genomics, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany;
authors.forename: Daniela
authors.initials: D
authors.lastname: Indenbirken
authors.affiliation: Retroviral Pathogenesis, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany;
authors.forename: Marion
authors.initials: M
authors.lastname: Ziegler
authors.affiliation: Retroviral Pathogenesis, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany;
authors.forename: Ursula
authors.initials: U
authors.lastname: Müller
authors.affiliation: 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.
authors.forename: Warren S
authors.initials: WS
authors.lastname: Alexander
authors.affiliation: Retroviral Pathogenesis, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany;
authors.forename: Carol
authors.initials: C
authors.lastname: Stocking
mesh_terms: D000818:Animals; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006412:Hematopoietic Stem Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008533:Megakaryocytes / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009190:Myelodysplastic Syndromes / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; C493726:Runx1 protein, mouse; D025521:Tumor Suppressor Proteins