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BCR-ABL maintains resistance of chronic myelogenous leukemia cells to apoptotic cell death
A McGahon1, R Bissonnette, M Schmitt
1Department of Biology, St Patrick's College, Kildare, Ireland.
Abstract:
Apoptosis is the major form of cell death associated with the action of chemotherapeutic agents on tumor cells, and therefore the expression of genes that interfere with apoptosis can have important consequences for the efficacy of therapeutic approaches. Here we show that K562, a chronic myelogenous leukemia (CML) cell line expressing the BCR-ABL fusion protein, are resistant to the induction of apoptosis by a number of agents and conditions. Antisense oligodeoxynucleotides corresponding to the translation start of bcr downregulate bcr-abl protein in these cells and render them susceptible to induction of apoptosis by chemotherapeutic agents or serum deprivation. Expression of a temperature sensitive v-Abl protein reverses the effects of the antisense oligonucleotides, such that the cells remain resistant to apoptosis at the permissive temperature. These data indicate that bcr-abl acts as an anti-apoptosis gene in CML cells and suggests that the effect is dependent on the abl kinase activity in this chimeric protein. Inhibition of bcr-abl to render CML cells susceptible to apoptosis can be combined with therapeutic drugs and/or treatment capable of inducing apoptosis to provide an effective strategy for elimination of these cells.
Insights
Chronic myelogenous leukemia (CML) cells resist apoptosis due to BCR-ABL. Inhibiting this protein with antisense oligodeoxynucleotides restores apoptosis sensitivity, offering a new therapeutic strategy for CML.
Area of Science:
- Oncology
- Molecular Biology
- Cell Death Research
Background:
- Apoptosis is crucial for chemotherapeutic efficacy against tumor cells.
- Gene expression influencing apoptosis significantly impacts treatment outcomes.
- Chronic myelogenous leukemia (CML) cells, particularly K562, exhibit resistance to apoptosis induction.
Purpose of the Study:
- To investigate the role of the BCR-ABL fusion protein in CML cell apoptosis resistance.
- To determine if inhibiting BCR-ABL can restore apoptosis sensitivity in CML cells.
- To explore therapeutic strategies targeting BCR-ABL for CML treatment.
Main Methods:
- Utilized K562 CML cell line expressing BCR-ABL.
- Employed antisense oligodeoxynucleotides targeting the BCR start site to downregulate BCR-ABL protein.
- Introduced temperature-sensitive v-Abl protein to assess the role of abl kinase activity.
Main Results:
- Antisense oligodeoxynucleotides targeting BCR successfully downregulated BCR-ABL protein in K562 cells.
- Downregulation of BCR-ABL rendered CML cells susceptible to apoptosis induction by chemotherapeutic agents and serum deprivation.
- Expression of temperature-sensitive v-Abl protein reversed the sensitization to apoptosis at permissive temperatures, highlighting the role of abl kinase activity.
Conclusions:
- BCR-ABL functions as an anti-apoptosis gene in CML cells.
- The anti-apoptotic effect of BCR-ABL is dependent on its abl kinase activity.
- Inhibiting BCR-ABL to restore apoptosis sensitivity presents a promising therapeutic strategy for CML, potentially combined with other apoptosis-inducing treatments.