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Therefore, measuring DNA breaks at rearrangement\u2010participating regions can provide a unique tool to identify and characterize susceptible individuals. Here, we developed a highly sensitive and low\u2010input DNA break mapping method, the first of its kind for patient samples. We then measured genome\u2010wide DNA breakage in normal cells of acute myeloid leukemia (AML) patients with <jats:italic>KMT2A<\/jats:italic> (previously <jats:italic>MLL<\/jats:italic>) rearrangements, compared to that of nonfusion AML individuals, as a means to evaluate individual susceptibility to gene rearrangements. DNA breakage at the <jats:italic>KMT2A<\/jats:italic> gene region was significantly greater in fusion\u2010driven remission individuals, as compared to nonfusion individuals. Moreover, we identified select topoisomerase II (TOP2)\u2010sensitive and CCCTC\u2010binding factor (CTCF)\/cohesin\u2010binding sites with preferential DNA breakage in fusion\u2010driven patients. Importantly, measuring DSBs at these sites, in addition to the <jats:italic>KMT2A<\/jats:italic> gene region, provided greater predictive power when assessing individual break susceptibility. We also demonstrated that low\u2010dose etoposide exposure further elevated DNA breakage at these regions in fusion\u2010driven AML patients, but not in nonfusion patients, indicating that these sites are preferentially sensitive to TOP2 activity in fusion\u2010driven AML patients. These results support that mapping of DSBs in patients enables discovery of novel break\u2010prone regions and monitoring of individuals susceptible to chromosomal abnormalities, and thus cancer. This will build the foundation for early detection of cancer\u2010susceptible individuals, as well as those preferentially susceptible to therapy\u2010related malignancies caused by treatment with TOP2 poisons.<\/jats:p>","DOI":"10.1002\/gcc.22993","type":"journal-article","created":{"date-parts":[[2021,8,18]],"date-time":"2021-08-18T07:20:05Z","timestamp":1629271205000},"page":"808-821","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Assessing acute myeloid leukemia susceptibility in rearrangement\u2010driven patients by <scp>DNA<\/scp> breakage at topoisomerase <scp>II<\/scp> and CCCTC\u2010binding factor\/cohesin binding sites"],"prefix":"10.1002","volume":"60","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5983-0621","authenticated-orcid":false,"given":"Naomi D.","family":"Atkin","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics University of Virginia School of 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