Identification of proapoptotic Bim as a tumor suppressor in neoplastic mast cells: role of KIT D816V and effects of various targeted drugs
Autor: | Winfried F. Pickl, Sabine Cerny-Reiterer, Michael Kneidinger, Matthias Mayerhofer, Christian Sillaber, Karl J. Aichberger, Alexander Gruze, Veronika Ferenc, Irina Mirkina, Peter Valent, Barbara Peter, Karoline V. Gleixner, Christian Baumgartner |
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Rok vydání: | 2009 |
Předmět: |
Myeloid
Gene Expression Apoptosis Biochemistry Bortezomib chemistry.chemical_compound hemic and lymphatic diseases Genes Tumor Suppressor Midostaurin Mast Cells Systemic mastocytosis RNA Small Interfering Bcl-2-Like Protein 11 Reverse Transcriptase Polymerase Chain Reaction Hematology Flow Cytometry Boronic Acids Immunohistochemistry Gene Expression Regulation Neoplastic Proto-Oncogene Proteins c-kit medicine.anatomical_structure Pyrazines biological phenomena cell phenomena and immunity Tyrosine kinase medicine.drug Tumor suppressor gene Immunology Blotting Western Antineoplastic Agents Biology Transfection Mastocytosis Systemic Proto-Oncogene Proteins medicine In Situ Nick-End Labeling Humans Protein Kinase Inhibitors Membrane Proteins Cell Biology medicine.disease Blotting Northern Staurosporine chemistry Mutation Cancer research Mast cell sarcoma Apoptosis Regulatory Proteins Obatoclax |
Zdroj: | Blood. 114(26) |
ISSN: | 1528-0020 |
Popis: | Systemic mastocytosis (SM) is a myeloid neoplasm involving mast cells (MCs) and their progenitors. In most cases, neoplastic cells display the D816V-mutated variant of KIT. KIT D816V exhibits constitutive tyrosine kinase (TK) activity and has been implicated in increased survival and growth of neoplastic MCs. Recent data suggest that the proapoptotic BH3-only death regulator Bim plays a role as a tumor suppressor in various myeloid neoplasms. We found that KIT D816V suppresses expression of Bim in Ba/F3 cells. The KIT D816–induced down-regulation of Bim was rescued by the KIT-targeting drug PKC412/midostaurin. Both PKC412 and the proteasome-inhibitor bortezomib were found to decrease growth and promote expression of Bim in MC leukemia cell lines HMC-1.1 (D816V negative) and HMC-1.2 (D816V positive). Both drugs were also found to counteract growth of primary neoplastic MCs. Furthermore, midostaurin was found to cooperate with bortezomib and with the BH3-mimetic obatoclax in producing growth inhibition in both HMC-1 subclones. Finally, a Bim-specific siRNA was found to rescue HMC-1 cells from PKC412-induced cell death. Our data show that KIT D816V suppresses expression of proapoptotic Bim in neoplastic MCs. Targeting of Bcl-2 family members by drugs promoting Bim (re)-expression, or by BH3-mimetics such as obatoclax, may be an attractive therapy concept in SM. |
Databáze: | OpenAIRE |
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