Ponatinib suppresses the development of myeloid and lymphoid malignancies associated with FGFR1 abnormalities
| العنوان: | Ponatinib suppresses the development of myeloid and lymphoid malignancies associated with FGFR1 abnormalities |
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| المؤلفون: | Haiyan Qin, Mingqiang Ren, Ruizhe Ren, John K. Cowell |
| المصدر: | Leukemia |
| بيانات النشر: | Springer Science and Business Media LLC, 2012. |
| سنة النشر: | 2012 |
| مصطلحات موضوعية: | Cancer Research, Myeloid, Blotting, Western, Fusion Proteins, bcr-abl, Fluorescent Antibody Technique, Apoptosis, Mice, SCID, Biology, Article, Immunoenzyme Techniques, Fusion gene, Mice, chemistry.chemical_compound, Leukemia, Promyelocytic, Acute, Mice, Inbred NOD, medicine, Animals, Humans, Immunoprecipitation, ponatinib, Receptor, Fibroblast Growth Factor, Type 1, Phosphorylation, myeloproliferative disease, Progenitor cell, Cell Proliferation, Mice, Inbred BALB C, Cell growth, Precursor Cells, B-Lymphoid, Cell Cycle, Ponatinib, Imidazoles, Myeloid leukemia, Hematology, Flow Cytometry, preclinical trial, medicine.disease, Xenograft Model Antitumor Assays, Molecular biology, Fusion protein, Pyridazines, stomatognathic diseases, Leukemia, FGFR1, medicine.anatomical_structure, Oncology, chemistry, Mutation, Cancer research, Female |
| الوصف: | 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. |
| تدمد: | 1476-5551 0887-6924 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::049f309cd5616292b6e05fe47b1a944aTest https://doi.org/10.1038/leu.2012.188Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....049f309cd5616292b6e05fe47b1a944a |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14765551 08876924 |
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