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    GABP transcription factor is required for development of chronic myelogenous leukemia via its control of PRKD2

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    PNAS_Yang_GABP_2312.full.pdf
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    Authors
    Yang, Zhongfa
    Zhang, Haojian
    Ma, Leyuan
    Peng, Cong
    Chen, Yaoyu
    Wang, Junling
    Green, Michael R.
    Li, Shaoguang
    Rosmarin, Alan G.
    UMass Chan Affiliations
    Program in Gene Function and Expression
    Program in Molecular Medicine
    Department of Medicine, Division of Hematology/Oncology
    Document Type
    Journal Article
    Publication Date
    2013-02-05
    Keywords
    GA-Binding Protein Transcription Factor
    Leukemia, Myelogenous, Chronic, BCR-ABL Positive
    Biochemistry, Biophysics, and Structural Biology
    Genetics and Genomics
    Hematology
    Hemic and Lymphatic Diseases
    Neoplasms
    Oncology
    
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    Link to Full Text
    http://dx.doi.org/10.1073/pnas.1212904110
    Abstract
    Hematopoietic stem cells (HSCs) are the source of all blood lineages, and HSCs must balance quiescence, self-renewal, and differentiation to meet lifelong needs for blood cell development. Transformation of HSCs by the breakpoint cluster region-ABL tyrosine kinase (BCR-ABL) oncogene causes chronic myelogenous leukemia (CML). The E-twenty six (ets) transcription factor GA binding protein (GABP) is a tetrameric transcription factor complex that contains GABPalpha and GABPbeta proteins. Deletion in bone marrow of Gabpa, the gene that encodes the DNA-binding component, caused cell cycle arrest in HSCs and profound loss of hematopoietic progenitor cells. Loss of Gabpalpha prevented development of CML, although mice continued to generate BCR-ABL-expressing Gabpalpha-null cells for months that were serially transplantable and contributed to all lineages in secondary recipients. A bioinformatic screen identified the serine-threonine kinase protein kinase D2 (PRKD2) as a potential effector of GABP in HSCs. Prkd2 expression was markedly reduced in Gabpalpha-null HSCs and progenitor cells. Reduced expression of PRKD2 or pharmacologic inhibition decreased cell cycling, and PRKD2 rescued growth of Gabpalpha-null BCR-ABL-expressing cells. Thus, GABP is required for HSC cell cycle entry and CML development through its control of PRKD2. This offers a potential therapeutic target in leukemia.
    Source
    Proc Natl Acad Sci U S A. 2013 Feb 5;110(6):2312-7. doi: 10.1073/pnas.1212904110. Link to article on publisher's site
    DOI
    10.1073/pnas.1212904110
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/44005
    PubMed ID
    23345428
    Related Resources
    Link to Article in PubMed
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    Publisher PDF posted as allowed by the publisher's author rights policy at http://www.pnas.org/site/aboutpnas/authorfaq.xhtml.

    ae974a485f413a2113503eed53cd6c53
    10.1073/pnas.1212904110
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