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    A therapeutically targetable mechanism of BCR-ABL-independent imatinib resistance in chronic myeloid leukemia

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    Authors
    Ma, Leyuan
    Shan, Yi
    Bai, Robert
    Xue, Liting
    Eide, Christopher A.
    Ou, Jianhong
    Zhu, Lihua Julie
    Hutchinson, Lloyd
    Cerny, Jan
    Khoury, Hanna Jean
    Sheng, Zhi
    Druker, Brian J.
    Li, Shaoguang
    Green, Michael R.
    Show allShow less
    UMass Chan Affiliations
    Department of Pathology
    Division of Hematology/Oncology, Department of Medicine
    Program in Molecular Medicine
    Program in Gene Function and Expression
    Document Type
    Journal Article
    Publication Date
    2014-09-03
    Keywords
    Bioinformatics
    Cancer Biology
    Hematology
    Neoplasms
    Oncology
    Pathology
    Therapeutics
    Translational Medical Research
    
    Metadata
    Show full item record
    Link to Full Text
    http://dx.doi.org/10.1126/scitranslmed.3009073
    Abstract
    Resistance to the BCR-ABL inhibitor imatinib mesylate (IM) poses a major problem for the treatment of chronic myeloid leukemia (CML). IM resistance often results from a secondary mutation in BCR-ABL that interferes with drug binding. However, in many instances, there is no mutation in BCR-ABL, and the basis of such BCR-ABL-independent IM resistance remains to be elucidated. To gain insight into BCR-ABL-independent IM resistance mechanisms, we performed a large-scale RNA interference screen and identified IM-sensitizing genes (IMSGs) whose knockdown renders BCR-ABL(+) cells IM-resistant. In these IMSG knockdown cells, RAF/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling is sustained after IM treatment because of up-regulation of PRKCH, which encodes the protein kinase C (PKC) family member PKCeta, an activator of CRAF. PRKCH is also up-regulated in samples from CML patients with BCR-ABL-independent IM resistance. Combined treatment with IM and trametinib, a U.S. Food and Drug Administration-approved MEK inhibitor, synergistically kills BCR-ABL(+) IMSG knockdown cells and prolongs survival in mouse models of BCR-ABL-independent IM-resistant CML. Finally, we showed that CML stem cells contain high levels of PRKCH, and this contributes to their intrinsic IM resistance. Combined treatment with IM and trametinib synergistically kills CML stem cells with negligible effect on normal hematopoietic stem cells. Collectively, our results identify a therapeutically targetable mechanism of BCR-ABL-independent IM resistance in CML and CML stem cells.
    Source
    L. Ma, Y. Shan, R. Bai, L. Xue, C. A. Eide, J. Ou, L. J. Zhu, L. Hutchinson, J. Cerny, H. J. Khoury, Z. Sheng, B. J. Druker, S. Li, M. R. Green, A therapeutically targetable mechanism of BCR-ABL–independent imatinib resistance in chronic myeloid leukemia. Sci. Transl. Med. 6, 252ra121 (2014). Link to article on publisher's site
    DOI
    10.1126/scitranslmed.3009073
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/44048
    PubMed ID
    25186176
    Related Resources
    Link to Article in PubMed
    ae974a485f413a2113503eed53cd6c53
    10.1126/scitranslmed.3009073
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