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Although we understand much about the function of both wildtype KMT2A and AFF1 multiprotein complexes, little is known about the molecular actions the two fusion proteins KMT2A::AFF1 and AFF1::KMT2A during the very early steps of disease onset and progression. Most published data have been generated in t(4;11) cell lines or transplanted mouse models, where exactly this process remains a black box. Here, we present the results of our efforts to establish a t(4;11) chromosomal translocation in human hematopoietic stem\/precursor cells by CRISPR\/Cas9. These genetically modified cells can be expanded over 5-6 months in vitro and their potential to differentiate was examined with IL-7 supplementation. The benefit of this model system is that (1) both reciprocal fusion proteins are concomitantly present, and (2) a molecular surveillance is possible at any timepoint through analysis of RNA, DNA or protein. Thus, the CRISPR\/Cas9 technique allowed us to create a bona fide model system to study the very early steps of leukemia onset at the molecular level. In conclusion, this approach is the fastest way to investigate and characterize\n                    <jats:italic>KMT2A<\/jats:italic>\n                    -r\u00a0fusions in primary human cells.\n                  <\/jats:p>","DOI":"10.1038\/s41375-025-02791-4","type":"journal-article","created":{"date-parts":[[2025,10,27]],"date-time":"2025-10-27T10:00:22Z","timestamp":1761559222000},"page":"72-86","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["CRISPR\/Cas9-mediated t(4;11) translocation in human hematopoietic stem\/precursor cells demonstrates plasticity to differentiate into either the myeloid or lymphoid lineage"],"prefix":"10.1038","volume":"40","author":[{"given":"T.","family":"Benz","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"P.","family":"Larghero","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C.","family":"Meyer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"T.","family":"Hanewald","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"D.","family":"Br\u00fcggmann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A.-E.","family":"Hentrich","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"F.","family":"Louwen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4870-3445","authenticated-orcid":false,"given":"R.","family":"Marschalek","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,10,27]]},"reference":[{"key":"2791_CR1","doi-asserted-by":"publisher","first-page":"10735","DOI":"10.1073\/pnas.88.23.10735","volume":"88","author":"S Ziemin-van der Poel","year":"1991","unstructured":"Ziemin-van der Poel S, McCabe NR, Gill HJ, Espinosa R 3rd, Patel Y, Harden A, et al. 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Blood Adv. 2025;9:4607\u201313.","journal-title":"Blood Adv"}],"container-title":["Leukemia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41375-025-02791-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41375-025-02791-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41375-025-02791-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T19:03:48Z","timestamp":1767985428000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41375-025-02791-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,27]]},"references-count":51,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,1]]}},"alternative-id":["2791"],"URL":"https:\/\/doi.org\/10.1038\/s41375-025-02791-4","relation":{},"ISSN":["0887-6924","1476-5551"],"issn-type":[{"value":"0887-6924","type":"print"},{"value":"1476-5551","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,27]]},"assertion":[{"value":"25 July 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 September 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 October 2025","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 October 2025","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"We declare no conflict of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"The Ethic Committee of the Frankfurt Goethe-University Frankfurt (\n                      \n                      ) has approved the use of umbilical cord blood from female donors after informed consent from all participants. (registration number 2021-499). All methods were performed in accordance with the relevant guidelines and regulations.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate\u2018 statement"}}]}}