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Ponatinib suppresses the development of myeloid and lymphoid malignancies associated with FGFR1 abnormalities.

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  • المؤلفون: Ren M;Ren M; Qin H; Ren R; Cowell JK
  • المصدر:
    Leukemia [Leukemia] 2013 Jan; Vol. 27 (1), pp. 32-40. Date of Electronic Publication: 2012 Jul 11.
  • نوع النشر :
    Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
  • اللغة:
    English
  • معلومة اضافية
    • المصدر:
      Publisher: Nature Publishing Group, Specialist Journals Country of Publication: England NLM ID: 8704895 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-5551 (Electronic) Linking ISSN: 08876924 NLM ISO Abbreviation: Leukemia Subsets: MEDLINE
    • بيانات النشر:
      Publication: 2000- : London : Nature Publishing Group, Specialist Journals
      Original Publication: [Baltimore, Md.] : Williams & Wilkins, [c1987-
    • الموضوع:
      Cell Proliferation/*drug effects ; Imidazoles/*therapeutic use ; Leukemia, Promyelocytic, Acute/*mortality ; Mutation/*genetics ; Precursor Cells, B-Lymphoid/*drug effects ; Pyridazines/*therapeutic use ; Receptor, Fibroblast Growth Factor, Type 1/*genetics; Animals ; Apoptosis/drug effects ; Blotting, Western ; Cell Cycle ; Female ; Flow Cytometry ; Fluorescent Antibody Technique ; Fusion Proteins, bcr-abl/genetics ; Humans ; Immunoenzyme Techniques ; Immunoprecipitation ; Leukemia, Promyelocytic, Acute/genetics ; Leukemia, Promyelocytic, Acute/prevention & control ; Mice ; Mice, Inbred BALB C ; Mice, Inbred NOD ; Mice, SCID ; Phosphorylation/drug effects ; Precursor Cells, B-Lymphoid/metabolism ; Precursor Cells, B-Lymphoid/pathology ; Xenograft Model Antitumor Assays
    • نبذة مختصرة :
      Myeloid and lymphoid malignancies associated with fibroblast growth factor receptor-1 (FGFR1) abnormalities are characterized by constitutively activated FGFR1 kinase and rapid transformation to acute myeloid leukemia and lymphoblastic lymphoma. Molecular targeted therapies have not been widely used for stem cell leukemia/lymphoma (SCLL). Ponatinib (AP24534), which potently inhibits native and mutant BCR-ABL, also targets the FGFR family. Using murine BaF3 cells, stably transformed with six different FGFR1 fusion genes, as well as human KG1 cells expressing activated chimeric FGFR1 and five newly established murine SCLL cell lines, we show that ponatinib (<50 nM) can effectively inhibit phosphoactivation of the fusion kinases and their downstream effectors, such as PLCγ, Stat5 and Src. Ponatinib also significantly extended survival of mice transplanted with different SCLL cell lines. Ponatinib administered at 30 mg/kg daily also significantly delayed, or even prevented, tumorigenesis of KG1 cells in xenotransplanted mice. Furthermore, we demonstrate that ponatinib specifically inhibits cell growth and clonogenicity of normal human CD34+ progenitor cells transformed by chimeric FGFR1 fusion kinases. Overall, our data provide convincing evidence to suggest that pharmacologic inhibition of FGFR1 fusion kinases with ponatinib is likely to be beneficial for patients with SCLL and perhaps for other human disorders associated with dysregulated FGFR1 activity.
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    • Grant Information:
      R01 CA076167 United States CA NCI NIH HHS; CA076167 United States CA NCI NIH HHS
    • الرقم المعرف:
      0 (Imidazoles)
      0 (Pyridazines)
      4340891KFS (ponatinib)
      EC 2.7.10.1 (Receptor, Fibroblast Growth Factor, Type 1)
      EC 2.7.10.2 (Fusion Proteins, bcr-abl)
    • الموضوع:
      Date Created: 20120712 Date Completed: 20130228 Latest Revision: 20211021
    • الموضوع:
      20250114
    • الرقم المعرف:
      PMC3629706
    • الرقم المعرف:
      10.1038/leu.2012.188
    • الرقم المعرف:
      22781593