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    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.

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    Authors
    Landry, Josette-Renee
    Bonadies, Nicolas
    Kinston, Sarah
    Knezevic, Kathy
    Wilson, Nicola K
    Oram, S Helen
    Janes, Mary E
    Piltz, Sandie
    Hammett, Michelle
    Carter, Jacinta
    Hamilton, Tina
    Donaldson, Ian J
    Lacaud, Georges
    Frampton, Jonathan
    Follows, George A
    Kouskoff, Valerie
    Göttgens, Berthold
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    Affiliation
    Department of Haematology, Cambridge Institute for Medical Research, Cambridge University, Cambridge, United Kingdom.
    Issue Date
    2009-06-04
    
    Metadata
    Show full item record
    Abstract
    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.
    Citation
    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. 2009, 113 (23):5783-92 Blood
    Journal
    Blood
    URI
    http://hdl.handle.net/10541/85222
    DOI
    10.1182/blood-2008-11-187757
    PubMed ID
    19171877
    Type
    Article
    Language
    en
    ISSN
    1528-0020
    ae974a485f413a2113503eed53cd6c53
    10.1182/blood-2008-11-187757
    Scopus Count
    Collections
    All Paterson Institute for Cancer Research
    Stem Cell and Haematopoiesis
    Stem Cell Biology

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