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The DNA Methyltransferase Inhibitor 5-Aza-4'-thio-2'-Deoxycytidine Induces C>G Transversions and Acute Lymphoid
Ryan M Bertoli1, Yang Jo Chung1, Michael J Difilippantonio2
1Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
Cancer Research
|June 4, 2024
Summary
DNA methyltransferase inhibitors (DNMTi) like Aza-TdCyd (ATC) can cause lymphoid leukemia by inducing C>G mutations. Deleting the Dck enzyme blocks this mutagenic effect, highlighting risks of DNMTi therapy.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- DNA methyltransferase inhibitors (DNMTi) are clinically used, hypothesizing they re-express tumor suppressor genes via cytosine demethylation.
- 5-Aza-4'-thio-2'-deoxycytidine (ATC) is a novel DNMTi with demonstrated anti-tumor effects in solid tumors.
Purpose of the Study:
- To investigate the therapeutic potential and safety of ATC in a murine model of myelodysplastic syndrome.
- To identify the molecular mechanisms underlying ATC's effects on bone marrow cells and healthy mice.
Main Methods:
- Murine transplantation model of myelodysplastic syndrome.
- Whole-exome sequencing to identify acquired mutations.
- In vitro treatment of human cells with ATC.
- Genetic deletion of Dck (cytidine salvage pathway enzyme).
Main Results:
- ATC treatment induced lymphoid leukemia in both transplanted and healthy mice.
- Whole-exome sequencing revealed approximately 1,000 C>G transversions in a 5'-NCG-3' context, affecting key leukemia genes.
- Similar C>G transversions were observed in human cells treated with ATC in vitro.
- Deletion of Dck abolished the observed C>G transversions, implicating the cytidine salvage pathway.
Conclusions:
- ATC exhibits a potent mutagenic and leukemogenic phenotype.
- The distinct mutation signature induced by ATC has significant implications for DNMTi research and clinical use.
- Understanding the role of the cytidine salvage pathway is crucial for mitigating ATC-induced genotoxicity.
