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• W3193702465 abstract "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 nonfusion 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 nonfusion 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 nonfusion 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." @default.
• W3193702465 created "2021-08-30" @default.
• W3193702465 creator A5009760322 @default.
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• W3193702465 creator A5068820428 @default.
• W3193702465 date "2021-08-26" @default.
• W3193702465 modified "2023-10-13" @default.
• W3193702465 title "Assessing acute myeloid leukemia susceptibility in rearrangement‐driven patients by <scp>DNA</scp> breakage at topoisomerase <scp>II</scp> and CCCTC‐binding factor/cohesin binding sites" @default.
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• W3193702465 doi "https://doi.org/10.1002/gcc.22993" @default.
• W3193702465 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/8511143" @default.
• W3193702465 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/34405474" @default.
• W3193702465 hasPublicationYear "2021" @default.
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