{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T18:34:31Z","timestamp":1789238071298,"version":"build-2803163510"},"reference-count":13,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T00:00:00Z","timestamp":1761609600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T00:00:00Z","timestamp":1761609600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["DA 1787\/3-1"],"award-info":[{"award-number":["DA 1787\/3-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005677","name":"Jos\u00e9 Carreras Leuk\u00e4mie-Stiftung","doi-asserted-by":"publisher","award":["03 R\/2020"],"award-info":[{"award-number":["03 R\/2020"]}],"id":[{"id":"10.13039\/501100005677","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005972","name":"Deutsche Krebshilfe","doi-asserted-by":"publisher","award":["70113643"],"award-info":[{"award-number":["70113643"]}],"id":[{"id":"10.13039\/501100005972","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Exp Hematol Oncol"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Reconstructing and understanding intra-tumor heterogeneity, the coexistence of multiple genetically distinct subclones within the tumor of a patient, and tumor development is essential for resolving carcinogenesis and for identifying mechanisms of therapy resistance. While bulk sequencing can provide a broad view on tumoral complexity\/heterogeneity of a patient, single-cell analysis remains essential to identify rare subclones that might drive chemotherapy resistance. In this study, we performed an integrated analysis of bulk and single-cell DNA sequencing data of core-binding factor acute myeloid leukemia patients, defined by the presence of a\n                    <jats:italic>RUNX1::RUNX1T1<\/jats:italic>\n                    or\n                    <jats:italic>CBFB::MYH11<\/jats:italic>\n                    fusion gene. By single-cell sequencing, we inferred tumor phylogenies for 8 patients at diagnosis including patient-specific somatic variants, somatic copy-number alterations and fusion genes, and studied clonal evolution under the pressure of chemotherapy for 3 patients. As a result, we developed an approach to reliably integrate subclonal somatic copy number alterations into phylogenetic trees and clonal evolution analysis, obtaining unprecedented resolution of intra-tumor heterogeneity in CBF AML. We were able to show that the fusion gene is among the earliest events of leukemogenesis at single-cell level. We identified remaining tumor clones in 6 patients with complete remission samples indicating incomplete eradication of the tumor clones. Here, we show that identifying the order of mutation acquisition can provide valuable insights into evolutionary history, offering a framework to improve drug selection in the era of targeted therapies.\n                  <\/jats:p>","DOI":"10.1186\/s40164-025-00718-4","type":"journal-article","created":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T15:48:20Z","timestamp":1761666500000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Resolving intra-tumor heterogeneity and clonal evolution of core-binding factor acute myeloid leukemia patients with single-cell resolution"],"prefix":"10.1186","volume":"14","author":[{"given":"Raphael","family":"Hablesreiter","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paulina M.","family":"Strzelecka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klara","family":"Kopp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia","family":"Estrada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Dolnik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marlon","family":"Tilgner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Coral","family":"Fustero-Torre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felicitas","family":"Thol","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian H.","family":"Heidel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Heuser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laleh","family":"Haghverdi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars","family":"Bullinger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Friederike","family":"Christen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederik","family":"Damm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,28]]},"reference":[{"key":"718_CR1","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1007\/978-3-030-91836-1_6","volume":"1361","author":"A Lagan\u00e0","year":"2022","unstructured":"Lagan\u00e0 A. Computational approaches for the investigation of intra-tumor heterogeneity and clonal evolution from bulk sequencing data in precision oncology applications. Adv Exp Med Biol. 2022;1361:101\u201318.","journal-title":"Adv Exp Med Biol"},{"key":"718_CR2","doi-asserted-by":"publisher","first-page":"1703","DOI":"10.1038\/s41375-022-01613-1","volume":"36","author":"JD Khoury","year":"2022","unstructured":"Khoury JD, et al. The 5th edition of the World Health Organization classification of haematolymphoid tumours: myeloid and histiocytic\/dendritic neoplasms. Leukemia. 2022;36:1703\u201319.","journal-title":"Leukemia"},{"key":"718_CR3","doi-asserted-by":"publisher","first-page":"1140","DOI":"10.1182\/blood-2018-05-852822","volume":"133","author":"F Christen","year":"2019","unstructured":"Christen F, et al. Genomic landscape and clonal evolution of acute myeloid leukemia with t(8;21): an international study on 331 patients. Blood. 2019;133:1140\u201351.","journal-title":"Blood"},{"key":"718_CR4","doi-asserted-by":"publisher","first-page":"1551","DOI":"10.1038\/ng.3709","volume":"48","author":"ZJ Faber","year":"2016","unstructured":"Faber ZJ, et al. The genomic landscape of core-binding factor acute myeloid leukemias. Nat Genet. 2016;48:1551\u20136.","journal-title":"Nat Genet"},{"key":"718_CR5","doi-asserted-by":"publisher","first-page":"1553","DOI":"10.1038\/s41375-019-0697-0","volume":"34","author":"S Opatz","year":"2020","unstructured":"Opatz S, et al. The clinical mutatome of core binding factor leukemia. Leukemia. 2020;34:1553\u201362.","journal-title":"Leukemia"},{"key":"718_CR6","doi-asserted-by":"publisher","first-page":"452","DOI":"10.1200\/JCO.23.01053","volume":"42","author":"D Noerenberg","year":"2024","unstructured":"Noerenberg D, et al. Genetic characterization of primary mediastinal B-cell lymphoma: pathogenesis and patient outcomes. J Clin Oncol. 2024;42:452\u201366.","journal-title":"J Clin Oncol"},{"key":"718_CR7","doi-asserted-by":"publisher","first-page":"1593","DOI":"10.1182\/blood.2021014108","volume":"139","author":"CM Arends","year":"2022","unstructured":"Arends CM, et al. Clonal hematopoiesis is associated with improved survival in patients with metastatic colorectal cancer from the FIRE-3 trial. Blood. 2022;139:1593\u20137.","journal-title":"Blood"},{"key":"718_CR8","doi-asserted-by":"publisher","first-page":"1378","DOI":"10.1038\/s41375-024-02253-3","volume":"38","author":"CM Arends","year":"2024","unstructured":"Arends CM, et al. Dynamics of clonal hematopoiesis under DNA-damaging treatment in patients with ovarian cancer. Leukemia. 2024;38:1378\u201389.","journal-title":"Leukemia"},{"key":"718_CR9","doi-asserted-by":"publisher","first-page":"4921","DOI":"10.1038\/s41467-023-40378-8","volume":"14","author":"E Sollier","year":"2023","unstructured":"Sollier E, Kuipers J, Takahashi K, Beerenwinkel N, Jahn K. Compass: joint copy number and mutation phylogeny reconstruction from amplicon single-cell sequencing data. Nat Commun. 2023;14:4921.","journal-title":"Nat Commun"},{"key":"718_CR10","doi-asserted-by":"publisher","first-page":"272","DOI":"10.1186\/s13059-023-03106-5","volume":"24","author":"P Sashittal","year":"2023","unstructured":"Sashittal P, Zhang H, Iacobuzio-Donahue CA, Raphael BJ. Condor: tumor phylogeny inference with a copy-number constrained mutation loss model. Genome Biol. 2023;24:272.","journal-title":"Genome Biol"},{"key":"718_CR11","doi-asserted-by":"publisher","first-page":"6342","DOI":"10.1182\/bloodadvances.2020002673","volume":"4","author":"N Jahn","year":"2020","unstructured":"Jahn N, et al. Genomic heterogeneity in core-binding factor acute myeloid leukemia and its clinical implication. Blood Adv. 2020;4:6342\u201352.","journal-title":"Blood Adv"},{"key":"718_CR12","doi-asserted-by":"publisher","first-page":"2753","DOI":"10.1182\/blood.2021013626","volume":"138","author":"M Heuser","year":"2021","unstructured":"Heuser M, et al. 2021 update on MRD in acute myeloid leukemia: a consensus document from the European LeukemiaNet MRD working party. Blood. 2021;138:2753\u201367.","journal-title":"Blood"},{"key":"718_CR13","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1038\/s41586-020-2864-x","volume":"587","author":"LA Miles","year":"2020","unstructured":"Miles LA, et al. Single-cell mutation analysis of clonal evolution in myeloid malignancies. Nature. 2020;587:477\u201382.","journal-title":"Nature"}],"container-title":["Experimental Hematology &amp; Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s40164-025-00718-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s40164-025-00718-4\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s40164-025-00718-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,29]],"date-time":"2025-10-29T03:02:45Z","timestamp":1761706965000},"score":1,"resource":{"primary":{"URL":"https:\/\/ehoonline.biomedcentral.com\/articles\/10.1186\/s40164-025-00718-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,28]]},"references-count":13,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["718"],"URL":"https:\/\/doi.org\/10.1186\/s40164-025-00718-4","relation":{},"ISSN":["2162-3619"],"issn-type":[{"value":"2162-3619","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,28]]},"assertion":[{"value":"16 March 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 October 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 October 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All study protocols were approved by the Institutional Review Boards at each participating center in accordance with the Declaration of Helsinki (Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin: EA1_271_14, Medizinische Hochschule Hannover (MHH): 936-2011). Each patient provided written informed consent for the research use of their specimens before enrollment.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"FD reports personal fees from AbbVie, Amgen, Astra Zeneca, BeiGene, Gilead, Incyte, Novartis, and Roche outside the submitted work. LB reports advisory roles for Abbvie, Amgen, Astellas, Bristol-Myers Squibb, Celgene, Daiichi Sankyo, Gilead, Hexal, Janssen, Jazz Pharmaceuticals, Menarini, Novartis, Pfizer, Sanofi, Servier; as well as research funding from Bayer, Jazz Pharmaceuticals. MH declares honoraria from Abbvie, Bristol Myers Squibb, Janssen, Jazz Pharmaceuticals, Pfizer, Qiagen, Servier, Sobi, paid consultancy for AvenCell, Abbvie, Astellas, Glycostem, Janssen, LabDelbert, Miltenyi, Novartis, Pfizer, PinotBio, Servier, and research funding to his institution from Abbvie, Servier, Astellas, BergenBio, Glycostem, Jazz Pharmaceuticals, Karyopharm, Loxo Oncology, Novartis, PinotBio.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"127"}}