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Oncogenic c-kit transcript is a target for binase
Vladimir A Mitkevich1, Irina Y Petrushanko, Olga V Kretova
1Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia.
Cell Cycle (Georgetown, Tex.)
|June 29, 2010
Summary
Binase, an RNase, selectively kills acute myelogenous leukemia cells expressing mutated c-Kit by degrading its mRNA. Inhibiting the c-Kit protein reduces this sensitivity, highlighting mRNA as the key target.
Area of Science:
- Molecular Biology
- Oncology
- Biochemistry
Background:
- Mutations in the c-Kit receptor tyrosine kinase are frequent in acute myelogenous leukemia (AML).
- The N822K point mutation in c-Kit confers interleukin-3 independent growth to myeloid progenitor cells (FDC-P1).
Purpose of the Study:
- To investigate the selective cytotoxic effects of binase (an RNase from Bacillus intermedius) on FDC-P1-N822K cells.
- To determine if the expression of the c-Kit oncogene is responsible for the observed sensitivity to binase.
- To explore the potential of targeting both the oncogenic protein and its mRNA for cancer therapy.
Main Methods:
- Culturing FDC-P1-N822K cells, which express the N822K c-Kit mutation.
- Treating cells with binase and imatinib (a c-Kit inhibitor).
- Assessing cell viability and apoptosis.
- Quantifying cellular RNA and c-Kit mRNA levels using quantitative RT-PCR.
- Utilizing green fluorescent protein as a marker for c-Kit oncoprotein expression.
Main Results:
- Binase exhibits selective cytotoxicity towards FDC-P1-N822K cells.
- Inhibition of the mutated c-Kit protein with imatinib significantly reduces cell sensitivity to binase-induced apoptosis.
- Binase treatment leads to a 41% reduction in c-Kit mRNA levels in treated cells.
- The elimination of c-Kit is identified as the critical factor for binase's selective cytotoxicity.
Conclusions:
- The activated mutant c-Kit transcript is a direct target for the toxic action of binase.
- Targeting both the oncogenic protein and its corresponding mRNA represents a promising strategy for eliminating malignant cells in AML.
