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Blood, 4 June 2009, Vol. 113, No. 23, pp. 5783-5792. Prepublished online as a Blood First Edition Paper on January 26, 2009; DOI 10.1182/blood-2008-11-187757. This Article Full Text Full Text (PDF) Supplemental Tables and Figures All Versions of this Article: blood-2008-11-187757v1 113/23/5783    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Google Scholar Articles by Landry, J.-R. Articles by Göttgens, B. PubMed PubMed Citation Articles by Landry, J.-R. Articles by Göttgens, B. Related Collections Hematopoiesis and Stem Cells Immunobiology Lymphoid Neoplasia Gene Therapy Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMATOPOIESIS AND STEM CELLS Expression of the leukemia oncogene Lmo2 is controlled by an array of tissue-specific elements dispersed over 100 kb and bound by Tal1/Lmo2, Ets, and Gata factors Josette-Renée Landry1,*, Nicolas Bonadies1,*, Sarah Kinston1, Kathy Knezevic1, Nicola K. Wilson1, S. Helen Oram1, Mary Janes1, Sandie Piltz1, Michelle Hammett1, Jacinta Carter1, Tina Hamilton1, Ian J. Donaldson1, Georges Lacaud2, Jonathan Frampton3, George Follows1, Valerie Kouskoff2, and Berthold Göttgens1 1 Department of Haematology, Cambridge Institute for Medical Research, Cambridge University, Cambridge; 2 Paterson Institute for Cancer Research, Christie Hospital, Manchester; and 3 Institute of Biomedical Research, The Medical School, University of Birmingham, Birmingham, United Kingdom The Lmo2 gene encodes a transcriptional cofactor critical for the development of hematopoietic stem cells. Ectopic LMO2 expression causes leukemia in T-cell acute lymphoblastic leukemia (T-ALL) patients and severe combined immunodeficiency patients undergoing retroviral gene therapy. Tightly controlled Lmo2 expression is therefore essential, yet no comprehensive analysis of Lmo2 regulation has been published so far. By comparative genomics, we identified 17 highly conserved noncoding elements, 9 of which revealed specific acetylation marks in chromatin-immunoprecipitation and microarray (ChIP-chip) assays performed across 250 kb of the Lmo2 locus in 11 cell types covering different stages of hematopoietic differentiation. All candidate regulatory regions were tested in transgenic mice. An extended LMO2 proximal promoter fragment displayed strong endothelial activity, while the distal promoter showed weak forebrain activity. Eight of the 15 distal candidate elements functioned as enhancers, which together recapitulated the full expression pattern of Lmo2, directing expression to endothelium, hematopoietic cells, tail, and forebrain. Interestingly, distinct combinations of specific distal regulatory elements were required to extend endothelial activity of the LMO2 promoter to yolk sac or fetal liver hematopoietic cells. Finally, Sfpi1/Pu.1, Fli1, Gata2, Tal1/Scl, and Lmo2 were shown to bind to and transactivate Lmo2 hematopoietic enhancers, thus identifying key upstream regulators and positioning Lmo2 within hematopoietic regulatory networks. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: It takes (LMO) 2 to tango Ross C. Hardison Blood 2009 113: 5693. [Full Text] [PDF] This article has been cited by other articles: R. C. Hardison It takes (LMO) 2 to tango Blood, June 4, 2009; 113(23): 5693 - 5693. [Full Text] [PDF] N. K. Wilson, D. Miranda-Saavedra, S. Kinston, N. Bonadies, S. D. Foster, F. Calero-Nieto, M. A. Dawson, I. J. Donaldson, S. Dumon, J. Frampton, et al. The transcriptional program controlled by the stem cell leukemia gene Scl/Tal1 during early embryonic hematopoietic development Blood, May 28, 2009; 113(22): 5456 - 5465. [Abstract] [Full Text] [PDF]

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