title: SCL/TAL1-mediated transcriptional network enhances megakaryocytic specification of human embryonic stem cells.
abstract: Human embryonic stem cells (hESCs) are a unique in vitro model for studying human developmental biology and represent a potential source for cell replacement strategies. Platelets can be generated from cord blood progenitors and hESCs; however, the molecular mechanisms and determinants controlling the in vitro megakaryocytic specification of hESCs remain elusive. We have recently shown that stem cell leukemia (SCL) overexpression accelerates the emergence of hemato-endothelial progenitors from hESCs and promotes their subsequent differentiation into blood cells with higher clonogenic potential. Given that SCL participates in megakaryocytic commitment, we hypothesized that it may potentiate megakaryopoiesis from hESCs. We show that ectopic SCL expression enhances the emergence of megakaryocytic precursors, mature megakaryocytes (MKs), and platelets in vitro. SCL-overexpressing MKs and platelets respond to different activating stimuli similar to their control counterparts. Gene expression profiling of megakaryocytic precursors shows that SCL overexpression renders a megakaryopoietic molecular signature. Connectivity Map analysis reveals that trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA), both histone deacetylase (HDAC) inhibitors, functionally mimic SCL-induced effects. Finally, we confirm that both TSA and SAHA treatment promote the emergence of CD34(+) progenitors, whereas valproic acid, another HDAC inhibitor, potentiates MK and platelet production. We demonstrate that SCL and HDAC inhibitors are megakaryopoiesis regulators in hESCs.
authors.affiliation: 1] Genomic Medicine Department, GENYO, Centre for Genomics and Oncological Research, Pfizer-University of Granada-Andalusian Regional Government, PTS Granada, Granada, Spain [2] Current address: Amarna Therapeutics SL. Seville, Spain.
authors.forename: Miguel G
authors.initials: MG
authors.lastname: Toscano
authors.affiliation: Genomic Oncology Department, GENYO, Centre for Genomics and Oncological Research, Pfizer-University of Granada-Andalusian Regional Government, PTS Granada, Granada, Spain.
authors.forename: Oscar
authors.initials: O
authors.lastname: Navarro-Montero
authors.affiliation: Genomic Oncology Department, GENYO, Centre for Genomics and Oncological Research, Pfizer-University of Granada-Andalusian Regional Government, PTS Granada, Granada, Spain.
authors.forename: Veronica
authors.initials: V
authors.lastname: Ayllon
authors.affiliation: Genomic Oncology Department, GENYO, Centre for Genomics and Oncological Research, Pfizer-University of Granada-Andalusian Regional Government, PTS Granada, Granada, Spain.
authors.forename: Veronica
authors.initials: V
authors.lastname: Ramos-Mejia
authors.affiliation: Genomic Oncology Department, GENYO, Centre for Genomics and Oncological Research, Pfizer-University of Granada-Andalusian Regional Government, PTS Granada, Granada, Spain.
authors.forename: Xiomara
authors.initials: X
authors.lastname: Guerrero-Carreno
authors.affiliation: 1] Genomic Oncology Department, GENYO, Centre for Genomics and Oncological Research, Pfizer-University of Granada-Andalusian Regional Government, PTS Granada, Granada, Spain [2] Josep Carreras Leukemia Research Institute and Cell Therapy Program, Facultat de Medicina, University of Barcelona, Barcelona, Spain.
authors.forename: Clara
authors.initials: C
authors.lastname: Bueno
authors.affiliation: Genomic Oncology Department, GENYO, Centre for Genomics and Oncological Research, Pfizer-University of Granada-Andalusian Regional Government, PTS Granada, Granada, Spain.
authors.forename: Tamara
authors.initials: T
authors.lastname: Romero
authors.affiliation: Genomic Oncology Department, GENYO, Centre for Genomics and Oncological Research, Pfizer-University of Granada-Andalusian Regional Government, PTS Granada, Granada, Spain.
authors.forename: Mar
authors.initials: M
authors.lastname: Lamolda
authors.affiliation: Genomic Medicine Department, GENYO, Centre for Genomics and Oncological Research, Pfizer-University of Granada-Andalusian Regional Government, PTS Granada, Granada, Spain.
authors.forename: Marien
authors.initials: M
authors.lastname: Cobo
authors.affiliation: Genomic Medicine Department, GENYO, Centre for Genomics and Oncological Research, Pfizer-University of Granada-Andalusian Regional Government, PTS Granada, Granada, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Martin
authors.affiliation: 1] Genomic Oncology Department, GENYO, Centre for Genomics and Oncological Research, Pfizer-University of Granada-Andalusian Regional Government, PTS Granada, Granada, Spain [2] Josep Carreras Leukemia Research Institute and Cell Therapy Program, Facultat de Medicina, University of Barcelona, Barcelona, Spain [3] Instituciò Catalana de Reserca i Estudis Avançats (ICREA), Barcelona, Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: Menendez
authors.affiliation: Genomic Oncology Department, GENYO, Centre for Genomics and Oncological Research, Pfizer-University of Granada-Andalusian Regional Government, PTS Granada, Granada, Spain.
authors.forename: Pedro J
authors.initials: PJ
authors.lastname: Real
mesh_terms: D018952:Antigens, CD34 / Q000235:genetics / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D002454:Cell Differentiation; D019070:Cell Lineage / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008533:Megakaryocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010957:Plasmids / Q000378:metabolism; D025941:Protein Interaction Mapping; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D034061:Thrombopoiesis / Q000187:drug effects / Q000235:genetics*; D014158:Transcription, Genetic; D014635:Valproic Acid / Q000494:pharmacology; D000077337:Vorinostat
chemical_list: D018952:Antigens, CD34; D051792:Basic Helix-Loop-Helix Proteins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D011518:Proto-Oncogene Proteins; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D014635:Valproic Acid; D000077337:Vorinostat; C067143:TAL1 protein, human; C012589:trichostatin A