Assessing AML susceptibility in rearrangement-driven patients by DNA breakage at topoisomerase II and CTCF/cohesin binding sites
| Autor: | Atkin, Naomi D., Raimer, Heather M., Wang, Zhenjia, Zang, Chongzhi, Wang, Yuh-Hwa |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Chromosome Aberrations
Gene Rearrangement Male CCCTC-Binding Factor Binding Sites DNA Repair Oncogene Proteins Fusion Chromosomal Proteins Non-Histone Genome Human Cell Cycle Proteins Histone-Lysine N-Methyltransferase Article DNA-Binding Proteins Leukemia Myeloid Acute DNA Topoisomerases Type II Chondroitin Sulfate Proteoglycans Humans DNA Breaks Double-Stranded Female Poly-ADP-Ribose Binding Proteins Myeloid-Lymphoid Leukemia Protein Etoposide HeLa Cells |
| Zdroj: | Genes Chromosomes Cancer |
| Popis: | An initiating DNA double strand break (DSB) event precedes the formation of cancer-driven chromosomal abnormalities, such as gene rearrangements. Therefore, measuring DNA breaks at rearrangement-participating regions can provide a unique tool to identify and characterize susceptible individuals. Here, we developed a highly sensitive and low-input DNA break mapping method, the first of its kind for patient samples. We then measured genome-wide DNA breakage in normal cells of acute myeloid leukemia (AML) patients with KMT2A (previously MLL) rearrangements, compared to that of non-fusion AML individuals, as a means to evaluate individual susceptibility to gene rearrangements. DNA breakage at the KMT2A gene region was significantly greater in fusion-driven remission individuals, as compared to non-fusion individuals. Moreover, we identified select topoisomerase II (TOP2)-sensitive and CCCTC-binding factor (CTCF)/cohesin binding sites with preferential DNA breakage in fusion-driven patients. Importantly, measuring DSBs at these sites, in addition to the KMT2A gene region, provided greater predictive power when assessing individual break susceptibility. We also demonstrated that low-dose etoposide exposure further elevated DNA breakage at these regions in fusion-driven AML patients, but not in non-fusion patients, indicating that these sites are preferentially sensitive to TOP2 activity in fusion-driven AML patients. These results support that mapping of DSBs in patients enables discovery of novel break-prone regions and monitoring of individuals susceptible to chromosomal abnormalities, and thus cancer. This will build the foundation for early detection of cancer-susceptible individuals, as well as those preferentially susceptible to therapy-related malignancies caused by treatment with TOP2 poisons. |
| Databáze: | OpenAIRE |
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