{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T07:00:01Z","timestamp":1790233201688,"version":"4.1.0"},"reference-count":60,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2020,6,15]],"date-time":"2020-06-15T00:00:00Z","timestamp":1592179200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000402","name":"Kay Kendall Leukaemia Fund","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/501100000402","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100016131","name":"The Howat Foundation","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/501100016131","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Cancer Research UK Glasgow Centre","award":["C596\/A18076"],"award-info":[{"award-number":["C596\/A18076"]}]},{"DOI":"10.13039\/501100018703","name":"Cancer Research UK Beatson Institute","doi-asserted-by":"publisher","award":["C596\/A17196"],"award-info":[{"award-number":["C596\/A17196"]}],"id":[{"id":"10.13039\/501100018703","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Yorkhill Children\u2019s Leukaemia Research Fund","award":["NA"],"award-info":[{"award-number":["NA"]}]},{"DOI":"10.13039\/501100001273","name":"Children with Cancer UK","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/501100001273","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Chromosomal rearrangements of the mixed lineage leukaemia (MLL, also known as KMT2A) gene on chromosome 11q23 are amongst the most common genetic abnormalities observed in human acute leukaemias. MLL rearrangements (MLLr) are the most common cytogenetic abnormalities in infant and childhood acute myeloid leukaemia (AML) and acute lymphocytic leukaemia (ALL) and do not normally acquire secondary mutations compared to other leukaemias. To model these leukaemias, we have used clustered regularly interspaced short palindromic repeats (CRISPR)\/Cas9 gene editing to induce MLL-AF9 (MA9) chromosomal rearrangements in murine hematopoietic stem and progenitor cell lines and primary cells. By utilizing a dual-single guide RNA (sgRNA) approach targeting the breakpoint cluster region of murine Mll and Af9 equivalent to that in human MA9 rearrangements, we show efficient de novo generation of MA9 fusion product at the DNA and RNA levels in the bulk population. The leukaemic features of MA9-induced disease were observed including increased clonogenicity, enrichment of c-Kit-positive leukaemic stem cells and increased MA9 target gene expression. This approach provided a rapid and reliable means of de novo generation of Mll-Af9 genetic rearrangements in murine haematopoietic stem and progenitor cells (HSPCs), using CRISPR\/Cas9 technology to produce a cellular model of MA9 leukaemias which faithfully reproduces many features of the human disease in vitro.<\/jats:p>","DOI":"10.3390\/ijms21124266","type":"journal-article","created":{"date-parts":[[2020,6,15]],"date-time":"2020-06-15T12:16:57Z","timestamp":1592223417000},"page":"4266","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["CRISPR Gene Editing of Murine Blood Stem and Progenitor Cells Induces MLL-AF9 Chromosomal Translocation and MLL-AF9 Leukaemogenesis"],"prefix":"10.3390","volume":"21","author":[{"given":"Evgenia","family":"Sarrou","sequence":"first","affiliation":[{"name":"Paul O\u2019Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow G12 0YN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Richmond","sequence":"additional","affiliation":[{"name":"Paul O\u2019Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow G12 0YN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9474-4507","authenticated-orcid":false,"given":"Ruaidhr\u00ed J.","family":"Carmody","sequence":"additional","affiliation":[{"name":"Centre for Immunobiology, Institute of Infection, Immunity &amp; Inflammation, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brenda","family":"Gibson","sequence":"additional","affiliation":[{"name":"Royal Hospital for Children, Glasgow G51 4TF, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7266-0890","authenticated-orcid":false,"given":"Karen","family":"Keeshan","sequence":"additional","affiliation":[{"name":"Paul O\u2019Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow G12 0YN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,6,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"5215","DOI":"10.1038\/onc.2016.30","article-title":"The molecular mechanics of mixed lineage leukemia","volume":"35","author":"Slany","year":"2016","journal-title":"Oncogene"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1038\/ng.3230","article-title":"The landscape of somatic mutations in infant MLL-rearranged acute lymphoblastic leukemias","volume":"47","author":"Andersson","year":"2015","journal-title":"Nat. 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