{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,30]],"date-time":"2025-11-30T22:09:09Z","timestamp":1764540549880,"version":"3.46.0"},"reference-count":33,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T00:00:00Z","timestamp":1764028800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T00:00:00Z","timestamp":1764028800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100003252","name":"Lund University","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100003252","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Extensive genetic and epigenetic variegation has been demonstrated in many malignancies. Importantly, their interplay has the potential to contribute to disease progression and treatment resistance. To shed light on the complex relationships between these different sources of intra-tumour heterogeneity, we explored their relative contributions to the evolutionary dynamics of Acute Lymphoblastic Leukaemia (ALL) in children with Down syndrome, which has particularly poor prognosis. We quantified the tumour propagating potential of genetically distinct sub-clones using serial transplantation assays and SNP-arrays. While most leukaemias were characterized by a single dominant subclone, others were highly heterogeneous. Importantly, we provide clear and direct evidence that genotypes and phenotypes with functional relevance to leukemic progression and treatment resistance can co-segregate within the disease. Hence, individual genetic lesions can be restricted to well-defined cell immunophenotypes, corresponding to different stages of the leukemic differentiation hierarchy and varied proliferation potentials. As a result of this difference in fitness, which can be accurately quantified via competitive transplantation assays, matching diagnostic, post-treatment, and relapse leukaemias can be dominated by different genotypes, including pre-leukemic clones persisting throughout the disease progression and treatment. Intriguingly, plasticity also appears to be a temporally defined property that can segregate with genotype. These results suggest that Down Syndrome ALL should be viewed as a complex matrix of cells exhibiting genetic and epigenetic heterogeneity that foster extensive clonal evolution and competition. Therapeutic intervention reshapes this \u2018eco-system\u2019 and may provide the right conditions for the preferential expansion of selected compartments and subsequently relapse.<\/jats:p>","DOI":"10.1038\/s41598-025-28779-9","type":"journal-article","created":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T17:47:15Z","timestamp":1764092835000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Complex genotype-phenotype relationships shape the response to treatment of down syndrome childhood acute lymphoblastic leukaemia"],"prefix":"10.1038","volume":"15","author":[{"given":"Christoph","family":"Lutz","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Virginia A.","family":"Turati","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruth","family":"Clifford","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Petter S.","family":"Woll","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Stiehl","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anders","family":"Castor","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sally A.","family":"Clark","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Helen","family":"Ferry","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Veronica","family":"Buckle","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andreas","family":"Trumpp","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anthony","family":"Ho","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Marciniak-Czochra","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Javier","family":"Herrero","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Schuh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sten Eirik W.","family":"Jacobsen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tariq","family":"Enver","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,11,25]]},"reference":[{"key":"28779_CR1","first-page":"223","volume":"2017 1","author":"R Rosenthal","year":"2016","unstructured":"Rosenthal, R., Mcgranahan, N., Herrero, J. & Swanton, C. Deciphering genetic intratumor heterogeneity and its impact on cancer evolution. Annu. Rev. Cancer Biol. 2017 1, 223\u2013240 (2016).","journal-title":"Annu. Rev. Cancer Biol."},{"key":"28779_CR2","doi-asserted-by":"publisher","unstructured":"Marusyk, A., Almendro, V. & Polyak, K. Intra-tumour heterogeneity: A looking glass for cancer? Nature Reviews Cancer vol. 12 323\u2013334 at (2012). https:\/\/doi.org\/10.1038\/nrc3261","DOI":"10.1038\/nrc3261"},{"key":"28779_CR3","doi-asserted-by":"publisher","unstructured":"Landau, D. A., Carter, S. L., Getz, G. & Wu, C. J. Clonal evolution in hematological malignancies and therapeutic implications. Leukemia vol. 28 34\u201343 at (2014). https:\/\/doi.org\/10.1038\/leu.2013.248","DOI":"10.1038\/leu.2013.248"},{"key":"28779_CR4","doi-asserted-by":"publisher","first-page":"356","DOI":"10.1038\/nature09650","volume":"469","author":"K Anderson","year":"2011","unstructured":"Anderson, K. et al. Genetic variegation of clonal architecture and propagating cells in leukaemia. Nature 469, 356\u2013361 (2011).","journal-title":"Nature"},{"key":"28779_CR5","doi-asserted-by":"publisher","first-page":"362","DOI":"10.1038\/nature09733","volume":"469","author":"F Notta","year":"2011","unstructured":"Notta, F. et al. Evolution of human BCR-ABL1 lymphoblastic leukaemia-initiating cells. Nature 469, 362\u2013367 (2011).","journal-title":"Nature"},{"key":"28779_CR6","doi-asserted-by":"publisher","unstructured":"Turati, V. A. et al. Chemotherapy induces canalization of cell state in childhood B-cell precursor acute lymphoblastic leukemia. Nat Cancer https:\/\/doi.org\/10.1038\/s43018-021-00219-3","DOI":"10.1038\/s43018-021-00219-3"},{"key":"28779_CR7","doi-asserted-by":"publisher","first-page":"849","DOI":"10.1016\/j.ccell.2016.11.002","volume":"30","author":"S Ebinger","year":"2016","unstructured":"Ebinger, S. et al. Characterization of Rare, Dormant, and Therapy-Resistant cells in acute lymphoblastic leukemia. Cancer Cell. 30, 849\u2013862 (2016).","journal-title":"Cancer Cell."},{"key":"28779_CR8","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2012.306","author":"C Lutz","year":"2013","unstructured":"Lutz, C. et al. Quiescent leukaemic cells account for minimal residual disease in childhood lymphoblastic leukaemia. Leukemia https:\/\/doi.org\/10.1038\/leu.2012.306 (2013).","journal-title":"Leukemia"},{"key":"28779_CR9","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1158\/0008-5472.BCD-19-0041","volume":"1","author":"E Waanders","year":"2020","unstructured":"Waanders, E. et al. Mutational landscape and patterns of clonal evolution in relapsed pediatric acute lymphoblastic leukemia. 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BioRxiv Prepr (2021).","DOI":"10.1101\/2020.12.22.423823"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-28779-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-28779-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-28779-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,30]],"date-time":"2025-11-30T22:02:05Z","timestamp":1764540125000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-28779-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,25]]},"references-count":33,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["28779"],"URL":"https:\/\/doi.org\/10.1038\/s41598-025-28779-9","relation":{},"ISSN":["2045-2322"],"issn-type":[{"type":"electronic","value":"2045-2322"}],"subject":[],"published":{"date-parts":[[2025,11,25]]},"assertion":[{"value":"20 March 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 November 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 November 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":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"Diagnostic and follow-up ALL bone marrow (BM) samples were obtained after informed consent from a patient\u2019s parents and\/or legal guardians at the Paediatrics Haematology Unit, Lund University Hospital, Sweden. Samples from 4 children with Down\u2019s ALL were analysed. All in vivo experimental protocols were approved by Germany\u2019s Home Office (permit number: G-108\/12), and experiments were performed in strict accordance with the relevant national regulations.\u00a0All methods are reported per ARRIVE guidelines.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}}],"article-number":"42018"}}