title: Tumor necrosis factor α-mediated inhibition of erythropoiesis involves GATA-1/GATA-2 balance impairment and PU.1 over-expression.
abstract: 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 (TNFα), 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 TNFα-mediated inhibition of erythropoiesis. CD34(+) hematopoietic stem/progenitor cells (HSPCs) were isolated from human cord blood. Erythropoiesis was achieved in vitro by stimulating cells with EPO. We show that TNFα clearly affected erythroid development, as assessed by May-Grünwald/Giemsa staining, flow cytometry analysis and fluorescent microscopy. The amount of hemoglobin-producing cells as well as the expression of GATA-1 target erythro-specific genes (EPO receptor, glycophorin A and globins) was found decreased after TNFα treatment of HSPC. In correlation, TNFα induced the expression of the transcription factors GATA-2 and PU.1, described as inhibitors of erythropoiesis. In this regard, TNFα 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 TNFα prevents EPO-mediated erythropoiesis of HSPC as an early event, by directly affecting erythroid cell development.
authors.affiliation: Laboratoire de Biologie Moléculaire et Cellulaire du Cancer, Hôpital Kirchberg, Rue Edward Steichen, Luxembourg.
authors.forename: Christine
authors.initials: C
authors.lastname: Grigorakaki
authors.forename: Franck
authors.initials: F
authors.lastname: Morceau
authors.forename: Sébastien
authors.initials: S
authors.lastname: Chateauvieux
authors.forename: Mario
authors.initials: M
authors.lastname: Dicato
authors.forename: Marc
authors.initials: M
authors.lastname: Diederich
mesh_terms: D002478:Cells, Cultured; D041905:Erythroid Cells / Q000187:drug effects; D004920:Erythropoiesis / Q000187:drug effects*; D004921:Erythropoietin / Q000494:pharmacology; D050982:GATA1 Transcription Factor / Q000378:metabolism*; D050989:GATA2 Transcription Factor / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D004921:Erythropoietin; D050982:GATA1 Transcription Factor; D050989:GATA2 Transcription Factor; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D000099232:Proto-Oncogene Protein Spi-1; C494688:GATA1 protein, human; C494711:GATA2 protein, human