title: SCL/TAL1 in Hematopoiesis and Cellular Reprogramming.
abstract: SCL, a transcription factor of the basic helix-loop-helix family, is a master regulator of hematopoiesis. Scl specifies lateral plate mesoderm to a hematopoietic fate and establishes boundaries by inhibiting the cardiac lineage. A combinatorial interaction between Scl and Vegfa/Flk1 sets in motion the first wave of primitive hematopoiesis. Subsequently, definitive hematopoietic stem cells (HSCs) emerge from the embryo proper via an endothelial-to-hematopoietic transition controlled by Runx1, acting with Scl and Gata2. Past this stage, Scl in steady state HSCs is redundant with Lyl1, a highly homologous factor. However, Scl is haploinsufficient in stress response, when a rare subpopulation of HSCs with very long term repopulating capacity is called into action. SCL activates transcription by recruiting a core complex on DNA that necessarily includes E2A/HEB, GATA1-3, LIM-only proteins LMO1/2, LDB1, and an extended complex comprising ETO2, RUNX1, ERG, or FLI1. These interactions confer multifunctionality to a complex that can control cell proliferation in erythroid progenitors or commitment to terminal differentiation through variations in single component. Ectopic SCL and LMO1/2 expression in immature thymocytes activates of a stem cell gene network and reprogram cells with a finite lifespan into self-renewing preleukemic stem cells (pre-LSCs), an initiating event in T-cell acute lymphoblastic leukemias. Interestingly, fate conversion of fibroblasts to hematoendothelial cells requires not only Scl and Lmo2 but also Gata2, Runx1, and Erg, indicating a necessary collaboration between these transcription factors for hematopoietic reprogramming. Nonetheless, full reprogramming into self-renewing multipotent HSCs may require additional factors and most likely, a permissive microenvironment.
authors.affiliation: Laboratory of Hematopoiesis and Leukemia, Institute of Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, QC, Canada. Electronic address: trang.hoang@umontreal.ca.
authors.forename: T
authors.initials: T
authors.lastname: Hoang
authors.affiliation: Laboratory of Hematopoiesis and Leukemia, Institute of Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, QC, Canada.
authors.forename: J A
authors.initials: JA
authors.lastname: Lambert
authors.affiliation: Laboratory of Hematopoiesis and Leukemia, Institute of Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, QC, Canada.
authors.forename: R
authors.initials: R
authors.lastname: Martin
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology*; D002454:Cell Differentiation; D065150:Cellular Reprogramming / Q000502:physiology*; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics / Q000378:metabolism; D050982:GATA1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006410:Hematopoiesis / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000502:physiology; D006801:Humans; D060588:LIM Domain Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism / Q000502:physiology*; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D060168:Thymocytes / Q000378:metabolism / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051792:Basic Helix-Loop-Helix Proteins; D050676:Core Binding Factor Alpha 2 Subunit; D050982:GATA1 Transcription Factor; D060588:LIM Domain Proteins; D011518:Proto-Oncogene Proteins; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; C085117:LMO2 protein, human; C489366:Tal1 protein, mouse; C067143:TAL1 protein, human
keywords: Cellular reprogramming; Developmental hematopoiesis; E2A/TCF3; HEB/TCF12; Hematopoietic stem cells; NOTCH1; Preleukemic stem cells; SCL/TAL1; Self-renewal; VEGF