title: The SCL/TAL1 Transcription Factor Represses the Stress Protein DDiT4/REDD1 in Human Hematopoietic Stem/Progenitor Cells.
abstract: Hematopoietic stem/progenitor cells (HSPCs) are regulated through numerous molecular mechanisms that have not been interconnected. The transcription factor stem cell leukemia/T-cell acute leukemia 1 (TAL1) controls human HSPC but its mechanism of action is not clarified. In this study, we show that knockdown (KD) or short-term conditional over-expression (OE) of TAL1 in human HSPC ex vivo, respectively, blocks and maintains hematopoietic potentials, affecting proliferation of human HSPC. Comparative gene expression analyses of TAL1/KD and TAL1/OE human HSPC revealed modifications of cell cycle regulators as well as previously described TAL1 target genes. Interestingly an inverse correlation between TAL1 and DNA damage-induced transcript 4 (DDiT4/REDD1), an inhibitor of the mammalian target of rapamycin (mTOR) pathway, is uncovered. Low phosphorylation levels of mTOR target proteins in TAL1/KD HSPC confirmed an interplay between mTOR pathway and TAL1 in correlation with TAL1-mediated effects of HSPC proliferation. Finally chromatin immunoprecipitation experiments performed in human HSPC showed that DDiT4 is a direct TAL1 target gene. Functional analyses showed that TAL1 represses DDiT4 expression in HSPCs. These results pinpoint DDiT4/REDD1 as a novel target gene regulated by TAL1 in human HSPC and establish for the first time a link between TAL1 and the mTOR pathway in human early hematopoietic cells. Stem Cells 2015;33:2268-2279.
authors: CEA, DSV-IRCM-SCSR-LSHL, UMR 967, équipe labellisée Ligue Nationale contre le Cancer, Fontenay-aux-Roses, Paris, France.|INSERM, U967, Fontenay-aux-Roses, Paris, France.|Université Paris Diderot, UMR 967, Fontenay-aux-Roses, Paris, France.|Université Paris-Sud, UMR 967, Fontenay-aux-Roses, Paris, France.
authors: Aissa
authors: A
authors: Benyoucef
authors: CEA, DSV-IRCM-SCSR-LSHL, UMR 967, équipe labellisée Ligue Nationale contre le Cancer, Fontenay-aux-Roses, Paris, France.|INSERM, U967, Fontenay-aux-Roses, Paris, France.|Université Paris Diderot, UMR 967, Fontenay-aux-Roses, Paris, France.|Université Paris-Sud, UMR 967, Fontenay-aux-Roses, Paris, France.
authors: Julien
authors: J
authors: Calvo
authors: CEA, DSV-IRCM-SCSR-LSHL, UMR 967, équipe labellisée Ligue Nationale contre le Cancer, Fontenay-aux-Roses, Paris, France.|INSERM, U967, Fontenay-aux-Roses, Paris, France.|Université Paris Diderot, UMR 967, Fontenay-aux-Roses, Paris, France.|Université Paris-Sud, UMR 967, Fontenay-aux-Roses, Paris, France.
authors: Laurent
authors: L
authors: Renou
authors: CEA, DSV-IRCM-SCSR-LSHL, UMR 967, équipe labellisée Ligue Nationale contre le Cancer, Fontenay-aux-Roses, Paris, France.|INSERM, U967, Fontenay-aux-Roses, Paris, France.|Université Paris Diderot, UMR 967, Fontenay-aux-Roses, Paris, France.|Université Paris-Sud, UMR 967, Fontenay-aux-Roses, Paris, France.
authors: Marie-Laure
authors: ML
authors: Arcangeli
authors: Department of Cell Biology, Erasmus MC, Rotterdam, The Netherlands.
authors: Anita
authors: A
authors: van den Heuvel
authors: Centre d'Investigation Clinique-BioThérapie, Institut Gustave Roussy, Villejuif, Paris, France.
authors: Sophie
authors: S
authors: Amsellem
authors: INSERM U1151-CNRS UMR 8253 Institut Necker Enfants-Malades (INEM), Université Paris Descartes, Paris, France.
authors: Maryam
authors: M
authors: Mehrpour
authors: Cell Therapy Unit and Clinical Investigation Center in Biotherapies, AP-HP, Saint-Louis Hospital, Paris, France.
authors: Jerome
authors: J
authors: Larghero
authors: INSERM, U967, Fontenay-aux-Roses, Paris, France.|Department of Cell Biology, Erasmus MC, Rotterdam, The Netherlands.|CEA, DSV-IRCM-SCSR-LHM, UMR967, Fontenay-aux-Roses, Paris, France.
authors: Eric
authors: E
authors: Soler
authors: CEA, DSV-IRCM-SCSR-LSHL, UMR 967, équipe labellisée Ligue Nationale contre le Cancer, Fontenay-aux-Roses, Paris, France.|INSERM, U967, Fontenay-aux-Roses, Paris, France.|Université Paris Diderot, UMR 967, Fontenay-aux-Roses, Paris, France.|Université Paris-Sud, UMR 967, Fontenay-aux-Roses, Paris, France.
authors: Irina
authors: I
authors: Naguibneva
authors: CEA, DSV-IRCM-SCSR-LSHL, UMR 967, équipe labellisée Ligue Nationale contre le Cancer, Fontenay-aux-Roses, Paris, France.|INSERM, U967, Fontenay-aux-Roses, Paris, France.|Université Paris Diderot, UMR 967, Fontenay-aux-Roses, Paris, France.|Université Paris-Sud, UMR 967, Fontenay-aux-Roses, Paris, France.
authors: Francoise
authors: F
authors: Pflumio
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D013234:Stem Cells / Q000378:metabolism*; D051822:T Cell Transcription Factor 1; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D006360:Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; D051822:T Cell Transcription Factor 1; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D014157:Transcription Factors; C469991:DDIT4 protein, human; C071236:STIL protein, human; C067143:TAL1 protein, human
keywords: DDiT4; Hematopoietic stem cells; Maintenance/self-renewal; SCL/TAL1