Cell-Autonomous Function of Runx1 Transcriptionally Regulates Mouse Megakaryocytic Maturation

Pencovich, Niv; Jaschek, Ram; Dicken, Joseph; Amit, Ayelet; Lotem, Joseph; Tanay, Amos; Groner, Yoram

doi:10.1371/journal.pone.0064248

Cited by 24 publications

(31 citation statements)

References 39 publications

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“…A large proportion of Runx1 target genes encode proteins that regulate adhesion and motility, although other mechanisms may be at play. Whereas some of the genes have been previously described to be direct Runx1 target genes (eg, Mpl, Hmga2, and Selp), 71,79,80 we have identified several novel Runx1 target genes, including Jam3, Plxcn1, Tek, and Ecm1. Interestingly, several common features of HSCs and Megs are known, including shared BM niches and critical interactions with endothelial cells.…”

Section: Identification Of Runx1-binding Sites In Gmp-like Cells and mentioning

confidence: 66%

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

Behrens

Triviai

Schwieger

et al. 2016

Blood

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• Runx1 is a key determinant of megakaryocyte cell-fate decisions in multipotent progenitors.• Runx1 downregulates celladhesion factors that promote residency of stem cells and megakaryocytes in their bone marrow niche.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. (Blood. 2016;127(26):3369-3381)

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Section: Identification Of Runx1-binding Sites In Gmp-like Cells and mentioning

confidence: 66%

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

Behrens

Triviai

Schwieger

et al. 2016

Blood

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“…RUNX1 binding to the NF-E2 1A promoter was previously demonstrated in polycythemia vera granulocytes and HEL cells, and NF-E2 expression has been shown to be positively regulated by RUNX1 [34]. More recently, NF-E2 was identified as a RUNX1 target in mouse fetal liver megakaryocytes by ChIP-sequencing analysis, and reduced NF-E2 expression was found in conditional RUNX-1-deficient mice [37]. In this work, we confirm NF-E2 regulation by wild-type RUNX1, and show that two FPD/AML RUNX1 mutants [10] lose the ability to mediate NF-E2 promoter activation.…”

Section: Discussionmentioning

confidence: 87%

Mechanisms underlying platelet function defect in a pedigree with familial platelet disorder with a predisposition to acute myelogenous leukemia: potential role for candidate RUNX1 targets

Glembotsky

Bluteau

Espasandin

et al. 2014

Journal of Thrombosis and Haemostasis

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To cite this article: Glembotsky AC, Bluteau D, Espasandin YR, Goette NP, Marta RF, Marin Oyarzun CP, Korin L, Lev PR, Laguens RP, Molinas FC, Raslova H, Heller PG. Mechanisms underlying platelet function defect in a pedigree with familial platelet disorder with a predisposition to acute myelogenous leukemia: potential role for candidate RUNX1 targets. J Thromb Haemost 2014; 12: 761-72 Summary. Background: Familial platelet disorder with a predisposition to acute myelogenous leukemia (FPD/ AML) is an inherited platelet disorder caused by a germline RUNX1 mutation and characterized by thrombocytopenia, a platelet function defect, and leukemia predisposition. The mechanisms underlying FPD/AML platelet dysfunction remain incompletely clarified. We aimed to determine the contribution of platelet structural abnormalities and defective activation pathways to the platelet phenotype. In addition, by using a candidate gene approach, we sought to identify potential RUNX1-regulated genes involved in these defects. Methods: Lumiaggregometry, a-granule and dense granule content and release, platelet ultrastructure, a IIb b 3 integrin activation and outside-in signaling were assessed in members of one FPD/AML pedigree. Expression levels of candidate genes were measured and luciferase reporter assays and chromatin immunoprecipitation were performed to study NF-E2 regulation by RUNX1. Results: A severe decrease in platelet aggregation, defective a IIb b 3 integrin activation and combined ad storage pool deficiency were found.However, whereas the number of dense granules was markedly reduced, a-granule content was heterogeneous. A trend towards decreased platelet spreading was found, and b 3 integrin phosphorylation was impaired, reflecting altered outside-in signaling. A decrease in the level of transcription factor p45 NF-E2 was shown in platelet RNA and lysates, and other deregulated genes included RAB27B and MYL9. RUNX1 was shown to bind to the NF-E2 promoter in primary megakaryocytes, and wild-type RUNX1, but not FPD/AML mutants, was able to activate NF-E2 expression. Conclusions: The FPD/AML platelet function defect represents a complex trait, and RUNX1 orchestrates platelet function by regulating diverse aspects of this process. This study highlights the RUNX1 target NF-E2 as part of the molecular network by which RUNX1 regulates platelet biogenesis and function.

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“…Another example of how RUNX1 can regulate the expression of the same gene, but with different partners, is exemplified by the analysis of the promoter for myeloproliferative leukaemia (MPL, virus oncogene, the TPO receptor) where RUNX1 interacts with the SIN3A corepressor complex in haematopoietic stem and progenitor cells, whilst it forms a complex with the transcription activator EP300 (E1A-binding protein p300) on the same promoter in MKs [107]. The co-occupancy of RUNX1 and EP300 on the promoter region of multiple key MK genes was later confirmed in a genome-wide ChIP-Seq study using primary murine MKs [108].…”

Section: Runx1 In Partnershipmentioning

confidence: 90%

Transcriptional Regulation of Platelet Formation: Harnessing the Complexity for Efficient Platelet Production In Vitro

Tijssen

Moreau

Ghevaert

2016

Molecular and Cellular Biology of Platelet Formation

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It is now common knowledge that specific repertoires of transcription factors (TFs) determine a cell's protein content and thereby its phenotype. The expression of a given TF is not necessarily cell specific, and many TFs play a pivotal role in several different cell types. For example, TAL1, FLI1, RUNX1, ERG and GATA2 are important regulators of stem cells, but also play a vital role in megakaryopoiesis. Although the megakaryocyte (MK) and its closest relative, the red blood cell, share key TFs like GATA1 and NFE2, the bifurcation between the two lineages has been associated with pairs of TFs that act as a toggle switch (such as FLI1 and KLF1). This chapter will summarise the current knowledge of key transcriptional regulators of MK differentiation and how some of these TFs, despite being expressed in several cell types, can impose MK cell identity. Since the discovery of TPO in 1994, our knowledge of MK biology and differentiation has increased exponentially, but we still lack a deep understanding of what triggers the transition from MK growth and maturation to proplatelet formation. We describe how some well-known TFs control the expression of proteins that play a pivotal role in the dramatic cytoplasmic and cytoskeletal events that accompany proplatelet formation. Finally, we show how TFs can be harnessed in a powerful way to produce MKs and, potentially, platelets in vitro for future clinical applications.

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Cell-Autonomous Function of Runx1 Transcriptionally Regulates Mouse Megakaryocytic Maturation

Cited by 24 publications

References 39 publications

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

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

Mechanisms underlying platelet function defect in a pedigree with familial platelet disorder with a predisposition to acute myelogenous leukemia: potential role for candidate RUNX1 targets

Transcriptional Regulation of Platelet Formation: Harnessing the Complexity for Efficient Platelet Production In Vitro

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