한빛사논문
- 조회233
Ryan M. Bertoli1*, Yang Jo Chung1*, Michael J. Difilippantonio2, Anthony Wokasch1, Madison R.B.Marasco1, Haley Klimaszewski1, Susannah Gammell1, Yuelin J. Zhu1, Robert L. Walker1, Dengchao Cao1, Ajay Khanna4, Matthew J. Walter4, James H. Doroshow2, Paul S. Meltzer1, and Peter D. Aplan1,3
1Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
2Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD.
3Myeloid Malignancies Program, National Institutes of Health, Bethesda, MD.
4Department of Medicine, Division of Oncology, Washington University School of Medicine, St Louis, MO, USA
*Equal contribution
Corresponding author: Peter D. Aplan MD
Abstract
DNA methyltransferase inhibitors (DNMTi), most commonly cytidine analogs, are compounds that decrease 5'-cytosine methylation. DNMTi are used clinically based on the hypothesis that cytosine demethylation will lead to re-expression of tumor suppressor genes. 5-Aza-4'-thio-2'-deoxycytidine (Aza TdCyd or ATC) is a recently described thiol substituted DNMTi that has been shown to have anti-tumor activity in solid tumor models. Here, we investigated the therapeutic potential of ATC in a murine transplantation model of myelodysplastic syndrome. ATC treatment led to transformation of transplanted wild-type bone marrow nucleated cells into lymphoid leukemia, and healthy mice treated with ATC also developed lymphoid leukemia. Whole exome sequencing revealed thousands of acquired mutations, almost all of which were C>G transversions in a specific 5'-NCG-3' context. These mutations involved dozens of genes involved in human lymphoid leukemia, such as Notch1, Pten, Pax5, Trp53, and Nf1. Human cells treated in vitro with ATC showed thousands of acquired C>G transversions in a similar context. Deletion of Dck, the rate-limiting enzyme for the cytidine salvage pathway, eliminated C>G transversions. Taken together, these findings demonstrate a highly penetrant mutagenic and leukemogenic phenotype associated with ATC.
논문정보
- Research article
- 2024년 06월 (BRIC 등록일 2024-06-07)
- 국외 연구진
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