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    Thrombopoietin/MPL participates in initiating and maintaining RUNX1-ETO acute myeloid leukemia via PI3K/AKT signaling

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    Authors
    Pulikkan, John A.
    Madera, Dmitri
    Xue, Liting
    Bradley, Paul
    Landrette, Sean F.
    Kuo, Ya-Huei
    Abbas, Saman
    Zhu, Lihua Julie
    Valk, Peter J.
    Castilla, Lucio H.
    UMass Chan Affiliations
    Program in Gene Function and Expression
    Document Type
    Journal Article
    Publication Date
    2012-07-26
    Keywords
    Leukemia, Myeloid, Acute
    Receptors, Thrombopoietin
    Core Binding Factor Alpha 2 Subunit
    Genetics and Genomics
    Hemic and Lymphatic Diseases
    
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    Link to Full Text
    http://dx.doi.org/10.1182/blood-2012-03-414649
    Abstract
    Oncogenic mutations in components of cytokine signaling pathways elicit ligand-independent activation of downstream signaling, enhancing proliferation and survival in acute myeloid leukemia (AML). The myeloproliferative leukemia virus oncogene, MPL, a homodimeric receptor activated by thrombopoietin (THPO), is mutated in myeloproliferative disorders but rarely in AML. Here we show that wild type MPL expression is increased in a fraction of human AML samples expressing RUNX1-ETO, a fusion protein created by chromosome translocation t(8;21), and that upregulation of Mpl expression in mice induces AML when co-expressed with RUNX1-ETO. The leukemic cells are sensitive to THPO, activating survival and proliferative responses. Mpl expression is not regulated by RUNX1-ETO in mouse hematopoietic progenitors or leukemic cells. Moreover, we find that activation of PI3K/AKT but not ERK/MEK pathway is a critical mediator of the MPL-directed antiapoptotic function in leukemic cells. Hence, this study provides evidence that upregulation of wild type MPL levels promotes leukemia development and maintenance through activation of the PI3K/AKT axis, and suggests that inhibitors of this axis could be effective for treatment of MPL-positive AML.
    Source
    Blood. 2012 Jul 26;120(4):868-79. Epub 2012 May 21. Link to article on publisher's site
    DOI
    10.1182/blood-2012-03-414649
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/43983
    PubMed ID
    22613795
    Related Resources
    Link to Article in PubMed
    ae974a485f413a2113503eed53cd6c53
    10.1182/blood-2012-03-414649
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