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Updated: Jun 21, 2026
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Published on: January 7, 2019
Controlling subcellular localization to alter function: Sending oncogenic Bcr-Abl to the nucleus causes apoptosis
Andrew S Dixon1, Mudit Kakar, Korbinian M H Schneider
1Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT 84108, United States.
Summary
Targeting the location of Bcr-Abl protein in chronic myelogenous leukemia (CML) cells can induce cell death. Introducing multiple nuclear localization signals (NLSs) to Bcr-Abl forces it into the nucleus, triggering apoptosis in leukemia cells.
Area of Science:
- Molecular biology
- Cell biology
- Cancer research
Background:
- Altering protein subcellular localization is a therapeutic strategy.
- Mislocalized proteins, such as Bcr-Abl in chronic myelogenous leukemia (CML), can drive disease progression.
- Nuclear localization of endogenous Bcr-Abl induces apoptosis in K562 leukemia cells.
Purpose of the Study:
- To investigate if ectopically expressed Bcr-Abl can induce apoptosis in K562 cells when directed to the nucleus.
- To determine the efficacy of nuclear localization signals (NLSs) in redirecting Bcr-Abl localization.
Main Methods:
- Subcloning of SV40 large T-antigen NLSs to Bcr-Abl, creating 1NLS-Bcr-Abl and 4NLS-Bcr-Abl constructs.
- Transfection of constructs into K562 human leukemia cells.
- Assessment of Bcr-Abl localization, apoptosis induction via morphologic determination, DNA staining, and caspase-3 assay.
Main Results:
- Only the 4NLS-Bcr-Abl construct effectively translocated to the nucleus.
- Bcr-Abl and 1NLS-Bcr-Abl localized to the cytoplasm, colocalizing with actin.
- 4NLS-Bcr-Abl induced apoptosis in K562 cells 24 hours post-transfection.
Conclusions:
- Ectopically expressed Bcr-Abl can induce apoptosis in leukemia cells by altering its subcellular localization.
- Multiple NLSs are necessary to overcome Bcr-Abl's actin binding and achieve nuclear localization.
- This study demonstrates a novel therapeutic approach for CML by manipulating Bcr-Abl localization.
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