{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T01:49:02Z","timestamp":1791251342357,"version":"4.1.0"},"reference-count":12,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2022,3,12]],"date-time":"2022-03-12T00:00:00Z","timestamp":1647043200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,3,12]],"date-time":"2022-03-12T00:00:00Z","timestamp":1647043200000},"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","id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010663","name":"H2020 European Research Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010663","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005972","name":"Deutsche Krebshilfe","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005972","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008434","name":"Mehr LEBEN f\u00fcr Krebskranke Kinder \u2013 Bettina-Br\u00e4u-Stiftung","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100008434","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100013294","name":"Deutsches Forschungszentrum f\u00fcr Gesundheit und Umwelt, Helmholtz Zentrum M\u00fcnchen","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100013294","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004189","name":"Max-Planck-Gesellschaft","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004189","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Hematol Oncol"],"published-print":{"date-parts":[[2022,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Acute myeloid leukemia (AML) patients suffer dismal prognosis upon treatment resistance. To study functional heterogeneity of resistance, we generated serially transplantable patient-derived xenograft (PDX) models from one patient with AML and twelve clones thereof, each derived from a single stem cell, as proven by genetic barcoding. Transcriptome and exome sequencing segregated clones according to their origin from relapse one or two. Undetectable for sequencing, multiplex fluorochrome-guided competitive in vivo treatment trials identified a subset of relapse two clones as uniquely resistant to cytarabine treatment. Transcriptional and proteomic profiles obtained from resistant PDX clones and refractory AML patients defined a 16-gene score that was predictive of clinical outcome in a large independent patient cohort. Thus, we identified novel genes related to cytarabine resistance and provide proof of concept that intra-tumor heterogeneity reflects inter-tumor heterogeneity in AML.<\/jats:p>","DOI":"10.1186\/s13045-022-01232-4","type":"journal-article","created":{"date-parts":[[2022,3,12]],"date-time":"2022-03-12T11:02:46Z","timestamp":1647082966000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Adverse stem cell clones within a single patient\u2019s tumor predict clinical outcome in AML patients"],"prefix":"10.1186","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1834-965X","authenticated-orcid":false,"given":"Christina","family":"Zeller","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1302-9083","authenticated-orcid":false,"given":"Daniel","family":"Richter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vindi","family":"Jurinovic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4128-5914","authenticated-orcid":false,"given":"Ilse A.","family":"Valtierra-Guti\u00e9rrez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashok Kumar","family":"Jayavelu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Mann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0393-6157","authenticated-orcid":false,"given":"Johannes W.","family":"Bagnoli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0588-1313","authenticated-orcid":false,"given":"Ines","family":"Hellmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9615-9432","authenticated-orcid":false,"given":"Tobias","family":"Herold","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4056-0550","authenticated-orcid":false,"given":"Wolfgang","family":"Enard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1956-2778","authenticated-orcid":false,"given":"Binje","family":"Vick","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1773-7677","authenticated-orcid":false,"given":"Irmela","family":"Jeremias","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,3,12]]},"reference":[{"issue":"3","key":"1232_CR1","doi-asserted-by":"publisher","first-page":"483","DOI":"10.1016\/j.ccell.2018.08.007","volume":"34","author":"AL Boyd","year":"2018","unstructured":"Boyd AL, Aslostovar L, Reid J, Ye W, Tanasijevic B, Porras DP, et al. Identification of chemotherapy-induced leukemic-regenerating cells reveals a transient vulnerability of human AML recurrence. Cancer Cell. 2018;34(3):483\u201398.","journal-title":"Cancer Cell"},{"issue":"7382","key":"1232_CR2","doi-asserted-by":"publisher","first-page":"506","DOI":"10.1038\/nature10738","volume":"481","author":"L Ding","year":"2012","unstructured":"Ding L, Ley TJ, Larson DE, Miller CA, Koboldt DC, Welch JS, et al. Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing. Nature. 2012;481(7382):506.","journal-title":"Nature"},{"issue":"7834","key":"1232_CR3","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1038\/s41586-020-2864-x","volume":"587","author":"LA Miles","year":"2020","unstructured":"Miles LA, Bowman RL, Merlinsky TR, Csete IS, Ooi AT, Durruthy-Durruthy R, et al. Single-cell mutation analysis of clonal evolution in myeloid malignancies. Nature. 2020;587(7834):477\u201382.","journal-title":"Nature"},{"issue":"6","key":"1232_CR4","doi-asserted-by":"publisher","first-page":"1265","DOI":"10.1016\/j.cell.2019.01.031","volume":"176","author":"P van Galen","year":"2019","unstructured":"van Galen P, Hovestadt V, Wadsworth MH II, Hughes TK, Griffin GK, Battaglia S, et al. Single-cell RNA-seq reveals AML hierarchies relevant to disease progression and immunity. Cell. 2019;176(6):1265\u201381.","journal-title":"Cell"},{"issue":"7661","key":"1232_CR5","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1038\/nature22993","volume":"547","author":"LI Shlush","year":"2017","unstructured":"Shlush LI, Mitchell A, Heisler L, Abelson S, Ng SW, Trotman-Grant A, et al. Tracing the origins of relapse in acute myeloid leukaemia to stem cells. Nature. 2017;547(7661):104.","journal-title":"Nature"},{"issue":"1","key":"1232_CR6","doi-asserted-by":"publisher","first-page":"5838","DOI":"10.1038\/s41598-021-84708-6","volume":"11","author":"JM Kempf","year":"2021","unstructured":"Kempf JM, Weser S, Bartoschek MD, Metzeler KH, Vick B, Herold T, et al. Loss-of-function mutations in the histone methyltransferase EZH2 promote chemotherapy resistance in AML. Sci Rep. 2021;11(1):5838.","journal-title":"Sci Rep"},{"issue":"12","key":"1232_CR7","doi-asserted-by":"publisher","first-page":"2577","DOI":"10.1038\/leu.2017.140","volume":"31","author":"A Elder","year":"2017","unstructured":"Elder A, Bomken S, Wilson I, Blair HJ, Cockell S, Ponthan F, et al. Abundant and equipotent founder cells establish and maintain acute lymphoblastic leukaemia. Leukemia. 2017;31(12):2577.","journal-title":"Leukemia"},{"key":"1232_CR8","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1016\/j.exphem.2020.09.188","volume":"91","author":"S Jacobs","year":"2020","unstructured":"Jacobs S, Ausema A, Zwart E, Weersing E, de Haan G, Bystrykh LV, et al. Detection of chemotherapy-resistant patient-derived acute lymphoblastic leukemia clones in murine xenografts using cellular barcodes. Exp Hematol. 2020;91:46\u201354.","journal-title":"Exp Hematol"},{"issue":"7478","key":"1232_CR9","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1038\/nature12830","volume":"504","author":"Q Li","year":"2013","unstructured":"Li Q, Bohin N, Wen T, Ng V, Magee J, Chen S-C, et al. Oncogenic Nras has bimodal effects on stem cells that sustainably increase competitiveness. Nature. 2013;504(7478):143\u20137.","journal-title":"Nature"},{"issue":"4","key":"1232_CR10","doi-asserted-by":"publisher","first-page":"504","DOI":"10.1038\/nm.2338","volume":"17","author":"K Weber","year":"2011","unstructured":"Weber K, Thomaschewski M, Warlich M, Volz T, Cornils K, Niebuhr B, et al. RGB marking facilitates multicolor clonal cell tracking. Nat Med. 2011;17(4):504.","journal-title":"Nat Med"},{"issue":"3","key":"1232_CR11","doi-asserted-by":"publisher","first-page":"456","DOI":"10.3324\/haematol.2017.178442","volume":"103","author":"T Herold","year":"2018","unstructured":"Herold T, Jurinovic V, Batcha AM, Bamopoulos SA, Rothenberg-Thurley M, Ksienzyk B, et al. A 29-gene and cytogenetic score for the prediction of resistance to induction treatment in acute myeloid leukemia. Haematologica. 2018;103(3):456\u201365.","journal-title":"Haematologica"},{"issue":"7728","key":"1232_CR12","doi-asserted-by":"publisher","first-page":"526","DOI":"10.1038\/s41586-018-0623-z","volume":"562","author":"JW Tyner","year":"2018","unstructured":"Tyner JW, Tognon CE, Bottomly D, Wilmot B, Kurtz SE, Savage SL, et al. Functional genomic landscape of acute myeloid leukaemia. Nature. 2018;562(7728):526\u201331.","journal-title":"Nature"}],"container-title":["Journal of Hematology &amp; Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13045-022-01232-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13045-022-01232-4\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13045-022-01232-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,3,12]],"date-time":"2022-03-12T11:34:07Z","timestamp":1647084847000},"score":1,"resource":{"primary":{"URL":"https:\/\/jhoonline.biomedcentral.com\/articles\/10.1186\/s13045-022-01232-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,12]]},"references-count":12,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2022,12]]}},"alternative-id":["1232"],"URL":"https:\/\/doi.org\/10.1186\/s13045-022-01232-4","relation":{},"ISSN":["1756-8722"],"issn-type":[{"value":"1756-8722","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,12]]},"assertion":[{"value":"24 September 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 January 2022","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 March 2022","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Written informed consent was obtained from the patient. The study was performed in accordance with the ethical standards of the responsible committee on human experimentation (written approval by the Research Ethics Boards of the medical faculty of Ludwig-Maximilians-Universit\u00e4t, Munich, number 068-08 and 222-10) and with the Helsinki Declaration of 1975, as revised in 2013.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"The authors declare that they have no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"25"}}