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
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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