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The T\u2010lymphocytes, B\u2010lymphocytes and the functionally normal hematopoietic stem cells (HSC), that is, CD34<jats:sup>+<\/jats:sup>\/CD38<jats:sup>\u2212<\/jats:sup>\/ALDH<jats:sup>+<\/jats:sup> cells for AML with rare\u2010ALDH<jats:sup>+<\/jats:sup> blasts (&lt;1.9% ALDH<jats:sup>+<\/jats:sup> cells) were defined as the nonleukemia compartments. WES identified 62 point\u2010mutations in the leukemia compartment derived from 12 AML\u2010patients at the time of diagnosis and 73 mutations in 3 matched relapse cases. Most patients (8\/12) showed 4 to 6 point\u2010mutations per sample at diagnosis. Other than the mutations in the recurrently mutated genes such as <jats:italic>DNMT3A<\/jats:italic>, <jats:italic>NRAS<\/jats:italic> and <jats:italic>KIT<\/jats:italic>, we were able to identify novel point\u2010mutations that have not yet been described in AML. Some leukemia\u2010specific mutations and cytogenetic abnormalities including DNMT3A(R882H), EZH2(I146T) and inversion(16) were also detectable in the respective T\u2010lymphocytes, B\u2010lymphocytes and HSC in 5\/12 patients, suggesting that preleukemia HSC might represent the source of leukemogenesis for these cases. The leukemic evolution was reconstructed for five cases with detectable preleukemia clones, which were tracked in follow\u2010up and relapse samples. Four of the five patients with detectable preleukemic mutations developed relapse. The presence of leukemia\u2010specific mutations in these nonleukemia compartments, especially after chemotherapy or after allogeneic stem cell transplantation, is highly relevant, as these could be responsible for relapse. This discovery may facilitate the identification of novel targets for long\u2010term cure.<\/jats:p>","DOI":"10.1002\/ijc.33461","type":"journal-article","created":{"date-parts":[[2021,1,11]],"date-time":"2021-01-11T02:55:32Z","timestamp":1610333732000},"page":"2825-2838","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Analysis of nonleukemic cellular subcompartments reconstructs clonal evolution of acute myeloid leukemia and identifies therapy\u2010resistant preleukemic clones"],"prefix":"10.1002","volume":"148","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9811-3916","authenticated-orcid":false,"given":"Borhan R.","family":"Saeed","sequence":"first","affiliation":[{"name":"Department of Internal Medicine V University of Heidelberg  Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda","family":"Manta","sequence":"additional","affiliation":[{"name":"Department of Internal 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