Transcriptional control of granulocyte and monocyte development

Friedman, Alan D.

doi:10.1038/sj.onc.1210764

Cited by 377 publications

(373 citation statements)

References 192 publications

(177 reference statements)

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“…In this study, Nonetheless, the action of TNF was observed in a heterogeneous hematopoietic cell population in which anemia was successfully mimicked. Indeed, TNF specifically inhibited erythropoiesis by acting directly on HSPCs, likely by affecting EPO activity.At the molecular level, this study indicates the effect of TNF on the combination of transcription factors that leads to physiological hematopoietic lineage commitment [35][36][37]. In erythropoiesis, the GATA-1 and GATA-2 transcription factors have essential roles, and a quantitative balance in their protein levels is required to achieve erythroid lineage A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 -17 -vivo, inhibits erythroid differentiation [54,55].…”

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confidence: 83%

Tumor necrosis factor alpha-mediated inhibition of erythropoiesis involves GATA-1/GATA-2 balance impairment and PU.1 over-expression

Grigorakaki

Morceau

Chateauvieux

et al. 2011

Biochemical Pharmacology

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Many physiological perturbations can cause anemia. In cancer patients, activation of the immune system leads to the production of proinflammatory cytokines including tumor necrosis factor alpha (TNF), that have been shown to inhibit red-cell production via poorly understood mechanisms. Treatment of anemia by human recombinant erythropoietin (EPO) is strongly suspected to induce tumor growth.This study focuses on the mechanisms involved in TNF-mediated inhibition of erythropoiesis. CD34 + hematopoietic stem/progenitor cells (HSPC) were isolated from human cord blood. Erythropoiesis was achieved in vitro by stimulating cells with EPO. We show that TNF clearly affected erythroid development, as assessed by May-Grünwald/Giemsa staining, flow cytometry analysis and fluorescent microscopy. The amount of hemoglobinproducing cells as well as the expression of GATA-1 target erythro-specific genes (EPO receptor, glycophorin A and globins) was found decreased after TNF treatment of HSPC. In correlation, TNF induced the expression of the transcription factors GATA-2 and PU.1, described as inhibitors of erythropoiesis. In this regard, TNF promoted the formation of the GATA-1/PU.1 complex that has been reported to block the transcriptional activity of GATA-1. Our results clearly demonstrate that TNF prevents EPO-mediated erythropoiesis of HSPC as an early event, by directly affecting erythroid cell development.Keywords: anemia; inflammation; TNF; GATA-1; GATA-2; PU.1Page 3 of 38 A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 -3 - IntroductionThe majority of tumors are largely infiltrated by inflammatory cells, such as myelomonocytes and macrophages [1]. In response to the inflammatory environment, these cells produce inflammatory mediators including chemokines and cytokines. These mediators are tightly associated with cancer progression in combination with genetic alterations [2]. One of them, the Tumor Necrosis Factor alpha (TNF), is widely found in the inflammationassociated cancer microenvironment [3][4][5][6]. Interestingly, because TNF is commonly present in cancer and inflammatory diseases, it has been implicated in cancer-and inflammationrelated anemia. Indeed, patients suffering from cancer and chronic inflammation are often anemic [7]. Moreover, in vitro and in vivo studies have led to the conclusion that TNF inhibits hematopoietic progenitors from undergoing erythroid differentiation [8][9][10][11][12][13][14][15]. Anti-TNF treatment is effectively used for the treatment of chronic inflammatory diseases, but leads to increased risk of infection [16,17]. Despite the beneficial effects of anti-TNF, this treatment may promote different types of cancers [18,19].Several events may trigger anemia, including iron deficiency, hemolysis and hemorrhage. In non-hematopo...

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confidence: 83%

Tumor necrosis factor alpha-mediated inhibition of erythropoiesis involves GATA-1/GATA-2 balance impairment and PU.1 over-expression

Grigorakaki

Morceau

Chateauvieux

et al. 2011

Biochemical Pharmacology

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“…44 EGFP þ cells expressed lower levels of Scl, Gata3 and Fli1 transcripts, whereas Gata1 and Gata2 were upregulated (Figure 5f). The transcript levels of Pu1 and c-fms, which have a critical role in differentiation to myeloid lineages, 45 were increased in EGFP þ cells. In contrast, transcripts encoding myeloperoxidase and lysozyme, involved in differentiation of more mature myeloid stages, were strongly downregulated, in agreement with the incomplete myeloid development observed in EGFP þ Tie2-Cre;N1ICD cells.…”

Section: E)mentioning

confidence: 98%

Notch1 regulates progenitor cell proliferation and differentiation during mouse yolk sac hematopoiesis

et al. 2014

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Loss-of-function studies have demonstrated the essential role of Notch in definitive embryonic mouse hematopoiesis. We report here the consequences of Notch gain-of-function in mouse embryo hematopoiesis, achieved by constitutive expression of Notch1 intracellular domain (N1ICD) in angiopoietin receptor tyrosine kinase receptor-2 (Tie2)-derived enhanced green fluorescence protein (EGFP þ ) hematovascular progenitors. At E9.5, N1ICD expression led to the absence of the dorsal aorta hematopoietic clusters and of definitive hematopoiesis. The EGFP þ transient multipotent progenitors, purified from E9.5 to 10.5 Tie2-Cre;N1ICD yolk sac (YS) cells, had strongly reduced hematopoietic potential, whereas they had increased numbers of hemogenic endothelial cells. Late erythroid cell differentiation stages and mature myeloid cells (Gr1 þ , MPO þ ) were also strongly decreased. In contrast, EGFP þ erythro-myeloid progenitors, immature and intermediate differentiation stages of YS erythroid and myeloid cell lineages, were expanded. Tie2-Cre;N1ICD YS had reduced numbers of CD41 þ þ megakaryocytes, and these produced reduced below-normal numbers of immature colonies in vitro and their terminal differentiation was blocked. Cells from Tie2-Cre;N1ICD YS had a higher proliferation rate and lower apoptosis than wild-type (WT) YS cells. Quantitative gene expression analysis of FACS-purified EGFP þ YS progenitors revealed upregulation of Notch1-related genes and alterations in genes involved in hematopoietic differentiation. These results represent the first in vivo evidence of a role for Notch signaling in YS transient definitive hematopoiesis. Our results show that constitutive Notch1 activation in Tie2 þ cells hampers YS hematopoiesis of E9.5 embryos and demonstrate that Notch signaling regulates this process by balancing the proliferation and differentiation dynamics of lineage-restricted intermediate progenitors.

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“…they repress the production of each other [7-9]. In the erythrocyte/megakaryocite lineage high expression levels of gene GATA-1 and low levels of PU.1 were detected [6,10]; conversely, in the granulocyte/macrophage lineage higher expression levels of PU.1 and low levels of GATA-1 were measured [5,11]. However, the initial progenitor cells stay in the third state that has low-level activation of both genes PU.1 and GATA-1 .…”

Section: Introductionmentioning

confidence: 99%

Mathematical modeling of GATA-switching for regulating the differentiation of hematopoietic stem cell

Tian

Smith‐Miles

2014

BMC Systems Biology

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BackgroundHematopoiesis is a highly orchestrated developmental process that comprises various developmental stages of the hematopoietic stem cells (HSCs). During development, the decision to leave the self-renewing state and selection of a differentiation pathway is regulated by a number of transcription factors. Among them, genes GATA-1 and PU.1 form a core negative feedback module to regulate the genetic switching between the cell fate choices of HSCs. Although extensive experimental studies have revealed the mechanisms to regulate the expression of these two genes, it is still unclear how this simple module regulates the genetic switching.MethodsIn this work we proposed a mathematical model to study the mechanisms of the GATA-PU.1 gene network in the determination of HSC differentiation pathways. We incorporated the mechanisms of GATA switch into the module, and developed a mathematical model that comprises three genes GATA-1, GATA-2 and PU.1. In addition, a novel multiple-objective optimization method was designed to infer unknown parameters in the proposed model by realizing different experimental observations. A stochastic model was also designed to describe the critical function of noise, due to the small copy numbers of molecular species, in determining the differentiation pathways.ResultsThe proposed deterministic model has successfully realized three stable steady states representing the priming and different progenitor cells as well as genetic switching between the genetic states under various experimental conditions. Using different values of GATA-1 synthesis rate for the GATA-1 protein availability in the chromatin sites during the time period of GATA switch, stochastic simulations for the first time have realized different proportions of cells leading to different developmental pathways under various experimental conditions.ConclusionsMathematical models provide testable predictions regarding the mechanisms and conditions for realizing different differentiation pathways of hematopoietic stem cells. This work represents the first attempt at using a discrete stochastic model to realize the decision of HSC differentiation pathways showing a multimodal distribution.

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Transcriptional control of granulocyte and monocyte development

Cited by 377 publications

References 192 publications

Tumor necrosis factor alpha-mediated inhibition of erythropoiesis involves GATA-1/GATA-2 balance impairment and PU.1 over-expression

Tumor necrosis factor alpha-mediated inhibition of erythropoiesis involves GATA-1/GATA-2 balance impairment and PU.1 over-expression

Notch1 regulates progenitor cell proliferation and differentiation during mouse yolk sac hematopoiesis

Mathematical modeling of GATA-switching for regulating the differentiation of hematopoietic stem cell

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