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Identifying DNA Mutations in Purified Hematopoietic Stem/Progenitor Cells
Published on: February 24, 2014
Attenuated DNA damage repair delays therapy-related myeloid neoplasms in a mouse model
Kit I Tong1, Kazushige Ota2, Akiyoshi Komuro2
1The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON, Canada M5G 2M9.
Abstract:
Therapy-related cancers are potentially fatal late life complications for patients who received radio- or chemotherapy. So far, the mouse model showing reduction or delay of these diseases has not been described. We found that the disruption of Aplf in mice moderately attenuated DNA damage repair and, unexpectedly, impeded myeloid neoplasms after exposure to ionizing radiation (IR). Irradiated mutant mice showed higher rates of p53-dependent cell death, fewer chromosomal translocations, and a delay in malignancy-induced mortality. Simultaneous deficiency of p53 abrogated IR-induced apoptosis and the benefit of impaired DNA repair on mortality in irradiated Aplf–/– mice. Depletion of APLF in non-tumorigenic human cells also markedly reduced the risk of radiation-induced chromosomal aberrations. We therefore conclude that proficient DNA damage repair may promote chromosomal aberrations in normal tissues after irradiation and induce malignant evolution, thus illustrating the potential benefit in sensitizing p53 function by manipulating DNA repair efficiency in cancer patients undergoing genotoxic therapies.
Insights
Disrupting DNA repair protein APLF in mice reduced therapy-related myeloid cancers after radiation. Impaired DNA repair and p53 function slowed malignancy, suggesting new therapeutic strategies for cancer patients.
Area of Science:
- Oncology
- Molecular Biology
- Radiation Biology
Background:
- Therapy-related cancers are serious late complications for patients undergoing radio- or chemotherapy.
- Developing effective mouse models to study and prevent these cancers remains a challenge.
Purpose of the Study:
- To investigate the role of the DNA repair protein APLF in the development of therapy-related cancers.
- To evaluate the potential of modulating DNA repair pathways for cancer prevention in patients.
Main Methods:
- Disruption of the Aplf gene in mice.
- Exposure of mice to ionizing radiation (IR).
- Assessment of DNA damage repair, p53-dependent cell death, chromosomal translocations, and malignancy development.
- Depletion of APLF in human non-tumorigenic cells to assess radiation-induced chromosomal aberrations.
Main Results:
- Mice lacking Aplf showed attenuated DNA damage repair and reduced myeloid neoplasms post-IR.
- Irradiated Aplf-deficient mice exhibited increased p53-dependent cell death, fewer chromosomal translocations, and delayed mortality.
- Simultaneous p53 deficiency negated the protective effects of impaired DNA repair in irradiated Aplf-deficient mice.
- APLF depletion in human cells decreased radiation-induced chromosomal aberrations.
Conclusions:
- Proficient DNA damage repair may contribute to chromosomal aberrations and malignant evolution in normal tissues after irradiation.
- Manipulating DNA repair efficiency, potentially by sensitizing p53 function, could offer therapeutic benefits for cancer patients undergoing genotoxic therapies.
- APLF deficiency presents a novel therapeutic target for mitigating therapy-related cancers.
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