{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T20:26:39Z","timestamp":1790713599988,"version":"4.1.0"},"reference-count":32,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2020,6,7]],"date-time":"2020-06-07T00:00:00Z","timestamp":1591488000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Interdisciplinary Centre for Clinical Research (IZKF)","award":["2383-0-0"],"award-info":[{"award-number":["2383-0-0"]}]},{"name":"Interdisciplinary Centre for Clinical Research (IZKF)","award":["2386-0-0"],"award-info":[{"award-number":["2386-0-0"]}]},{"name":"Wuerttembergischer Krebspreis","award":["..."],"award-info":[{"award-number":["..."]}]},{"name":"Clinician Scientist Program of the Faculty of Medicine Tuebingen","award":["..."],"award-info":[{"award-number":["..."]}]},{"DOI":"10.13039\/501100005972","name":"Deutsche Krebshilfe","doi-asserted-by":"publisher","award":["Max Eder Junior Research Group Grant, 70112548"],"award-info":[{"award-number":["Max Eder Junior Research Group Grant, 70112548"]}],"id":[{"id":"10.13039\/501100005972","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Ministry of Science, Research and the Arts Baden-Wuerttemberg","award":["Margarete-von-Wrangell fellowship"],"award-info":[{"award-number":["Margarete-von-Wrangell fellowship"]}]},{"DOI":"10.13039\/501100002347","name":"Bundesministerium f\u00fcr Bildung und Forschung","doi-asserted-by":"publisher","award":["decipherPD transnational consortium on Epigenomics of Complex Diseases, 01KU1503"],"award-info":[{"award-number":["decipherPD transnational consortium on Epigenomics of Complex Diseases, 01KU1503"]}],"id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Mixed lineage leukemia (MLL) (KMT2A) rearrangements (KMT2Ar) play a crucial role in leukemogenesis. Dependent on age, major differences exist regarding disease frequency, main fusion partners and prognosis. In infants, up to 80% of acute lymphoid leukemia (ALL) bear a MLL translocation and half of them are t(4;11), resulting in a poor prognosis. In contrast, in adults only 10% of acute myeloid leukemia (AML) bear t(9;11) with an intermediate prognosis. The reasons for these differences are poorly understood. Recently, we established an efficient CRISPR\/Cas9-based KMT2Ar model in hematopoietic stem and progenitor cells (HSPCs) derived from human cord blood (huCB) and faithfully mimicked the underlying biology of the disease. Here, we applied this model to HSPCs from adult bone marrow (huBM) to investigate the impact of the cell of origin and fusion partner on disease development. Both genome-edited infant and adult KMT2Ar cells showed monoclonal outgrowth with an immature morphology, myelomonocytic phenotype and elevated KMT2Ar target gene expression comparable to patient cells. Strikingly, all KMT2Ar cells presented with indefinite growth potential except for MLL-AF4 huBM cells ceasing proliferation after 80 days. We uncovered FFAR2, an epigenetic tumor suppressor, as potentially responsible for the inability of MLL-AF4 to immortalize adult cells under myeloid conditions.<\/jats:p>","DOI":"10.3390\/cancers12061487","type":"journal-article","created":{"date-parts":[[2020,6,9]],"date-time":"2020-06-09T06:34:16Z","timestamp":1591684456000},"page":"1487","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Only Hematopoietic Stem and Progenitor Cells from Cord Blood Are Susceptible to Malignant Transformation by MLL-AF4 Translocations"],"prefix":"10.3390","volume":"12","author":[{"given":"Kathy-Ann","family":"Secker","sequence":"first","affiliation":[{"name":"Department of Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tuebingen, 72076 Tuebingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lukas","family":"Bruns","sequence":"additional","affiliation":[{"name":"Department of Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tuebingen, 72076 Tuebingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hildegard","family":"Keppeler","sequence":"additional","affiliation":[{"name":"Department of Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tuebingen, 72076 Tuebingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johan","family":"Jeong","sequence":"additional","affiliation":[{"name":"Synthego Corporation, Menlo Park, CA 94025, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1488-9096","authenticated-orcid":false,"given":"Thomas","family":"Hentrich","sequence":"additional","affiliation":[{"name":"Institute of Medical Genetics and Applied Genomics, University of Tuebingen, 72076 Tuebingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9242-2096","authenticated-orcid":false,"given":"Julia M.","family":"Schulze-Hentrich","sequence":"additional","affiliation":[{"name":"Institute of Medical Genetics and Applied Genomics, University of Tuebingen, 72076 Tuebingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Mankel","sequence":"additional","affiliation":[{"name":"Institute of Pathology and Neuropathology, University of Tuebingen, 72076 Tuebingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Falko","family":"Fend","sequence":"additional","affiliation":[{"name":"Institute of Pathology and Neuropathology, University of Tuebingen, 72076 Tuebingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominik","family":"Schneidawind","sequence":"additional","affiliation":[{"name":"Department of Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tuebingen, 72076 Tuebingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7333-8980","authenticated-orcid":false,"given":"Corina","family":"Schneidawind","sequence":"additional","affiliation":[{"name":"Department of Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tuebingen, 72076 Tuebingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,6,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1038\/leu.2017.213","article-title":"The MLL recombinome of acute leukemias in 2017","volume":"32","author":"Meyer","year":"2018","journal-title":"Leukemia"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1909","DOI":"10.1016\/S0140-6736(02)08782-2","article-title":"Outcome of treatment in childhood acute lymphoblastic leukaemia with rearrangements of the 11q23 chromosomal region","volume":"359","author":"Pui","year":"2002","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1007\/BF02983811","article-title":"The role of the MLL gene in infant leukemia","volume":"78","author":"Eguchi","year":"2003","journal-title":"Int. J. Hematol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1182\/blood.V77.3.440.440","article-title":"Clinical characteristics and treatment outcome of childhood acute lymphoblastic leukemia with the t(4;11)(q21;q23): A collaborative study of 40 cases","volume":"77","author":"Pui","year":"1991","journal-title":"Blood"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2406","DOI":"10.1182\/blood-2015-08-665547","article-title":"Acquisition of a CD19-negative myeloid phenotype allows immune escape of MLL-rearranged B-ALL from CD19 CAR-T-cell therapy","volume":"127","author":"Gardner","year":"2016","journal-title":"Blood"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3705","DOI":"10.1182\/blood.V82.12.3705.3705","article-title":"Rearrangements of the MLL gene in therapy-related acute myeloid leukemia in patients previously treated with agents targeting DNA-topoisomerase II","volume":"82","author":"Super","year":"1993","journal-title":"Blood"},{"key":"ref_7","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. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1038\/nm.4439","article-title":"The molecular landscape of pediatric acute myeloid leukemia reveals recurrent structural alterations and age-specific mutational interactions","volume":"24","author":"Bolouri","year":"2018","journal-title":"Nat. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1116","DOI":"10.1038\/leu.2012.343","article-title":"MLL-AF9-mediated immortalization of human hematopoietic cells along different lineages changes during ontogeny","volume":"27","author":"Horton","year":"2013","journal-title":"Leukemia"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2388","DOI":"10.1182\/bloodadvances.2019000554","article-title":"The efficiency of murine MLL-ENL-driven leukemia initiation changes with age and peaks during neonatal development","volume":"3","author":"Li","year":"2019","journal-title":"Blood Adv."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1126\/science.1139851","article-title":"Modeling the initiation and progression of human acute leukemia in mice","volume":"316","author":"Barabe","year":"2007","journal-title":"Science"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1683","DOI":"10.1182\/blood-2015-05-646398","article-title":"MLL leukemia induction by genome editing of human CD34+ hematopoietic cells","volume":"126","author":"Buechele","year":"2015","journal-title":"Blood"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1016\/j.ccr.2008.04.020","article-title":"Microenvironment determines lineage fate in a human model of MLL-AF9 leukemia","volume":"13","author":"Wei","year":"2008","journal-title":"Cancer Cell"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Secker, K.A., Keppeler, H., Duerr-Stoerzer, S., Schmid, H., Schneidawind, D., Hentrich, T., Schulze-Hentrich, J.M., Mankel, B., Fend, F., and Schneidawind, C. (2019). Inhibition of DOT1L and PRMT5 promote synergistic anti-tumor activity in a human MLL leukemia model induced by CRISPR\/Cas9. Oncogene.","DOI":"10.1038\/s41388-019-0937-9"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"832","DOI":"10.1182\/bloodadvances.2017013748","article-title":"MLL leukemia induction by t(9;11) chromosomal translocation in human hematopoietic stem cells using genome editing","volume":"2","author":"Schneidawind","year":"2018","journal-title":"Blood Adv."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1182\/blood-2014-03-563304","article-title":"Identification of CD34+ and CD34- leukemia-initiating cells in MLL-rearranged human acute lymphoblastic leukemia","volume":"125","author":"Aoki","year":"2015","journal-title":"Blood"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1038\/sj.leu.2400933","article-title":"Acute myeloid leukemia with 11q23 translocations: Myelomonocytic immunophenotype by multiparameter flow cytometry","volume":"12","author":"Baer","year":"1998","journal-title":"Leukemia"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"820","DOI":"10.1158\/1535-7163.MCT-06-0650","article-title":"Transcript and protein expression profiles of the NCI-60 cancer cell panel: An integromic microarray study","volume":"6","author":"Shankavaram","year":"2007","journal-title":"Mol. Cancer Ther."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2529","DOI":"10.1200\/JCO.2009.23.4732","article-title":"Clinical utility of microarray-based gene expression profiling in the diagnosis and subclassification of leukemia: Report from the International Microarray Innovations in Leukemia Study Group","volume":"28","author":"Haferlach","year":"2010","journal-title":"J. Clin. Oncol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"9534","DOI":"10.1021\/acs.jmedchem.8b00855","article-title":"Discovery of a Potent Thiazolidine Free Fatty Acid Receptor 2 Agonist with Favorable Pharmacokinetic Properties","volume":"61","author":"Hansen","year":"2018","journal-title":"J. Med. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1336","DOI":"10.1038\/bjc.2017.307","article-title":"Ffar2 expression regulates leukaemic cell growth in vivo","volume":"117","author":"Bindels","year":"2017","journal-title":"Br. J. Cancer"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1002\/ijc.31366","article-title":"Loss of FFAR2 promotes colon cancer by epigenetic dysregulation of inflammation suppressors","volume":"143","author":"Pan","year":"2018","journal-title":"Int. J. Cancer"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1016\/j.ccell.2015.06.003","article-title":"The H3K4-Methyl Epigenome Regulates Leukemia Stem Cell Oncogenic Potential","volume":"28","author":"Wong","year":"2015","journal-title":"Cancer Cell"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1038\/nchembio.2384","article-title":"Targeting S-adenosylmethionine biosynthesis with a novel allosteric inhibitor of Mat2A","volume":"13","author":"Quinlan","year":"2017","journal-title":"Nat. Chem. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.ccr.2011.06.009","article-title":"Selective killing of mixed lineage leukemia cells by a potent small-molecule DOT1L inhibitor","volume":"20","author":"Daigle","year":"2011","journal-title":"Cancer Cell"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1038\/nchembio.1810","article-title":"A selective inhibitor of PRMT5 with in vivo and in vitro potency in MCL models","volume":"11","author":"Kuplast","year":"2015","journal-title":"Nat. Chem. Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1021\/acsmedchemlett.5b00380","article-title":"Structure and Property Guided Design in the Identification of PRMT5 Tool Compound EPZ015666","volume":"7","author":"Duncan","year":"2016","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_28","unstructured":"Bushnell, B. (2020, May 24). BBMap: A Fast, Accurate, Splice-Aware Aligner, Available online: https:\/\/www.osti.gov\/servlets\/purl\/1241166."},{"key":"ref_29","unstructured":"Andrew, S. (2020, May 24). FastQC: A Quality Control Tool for High Throughput Sequence Data. Available online: http:\/\/www.bioinformatics.babraham.ac.uk\/projects\/fastqc."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1093\/bioinformatics\/bts635","article-title":"STAR: Ultrafast universal RNA-seq aligner","volume":"29","author":"Dobin","year":"2013","journal-title":"Bioinformatics"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2","volume":"15","author":"Love","year":"2014","journal-title":"Genome Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"882","DOI":"10.1093\/bioinformatics\/bts034","article-title":"The sva package for removing batch effects and other unwanted variation in high-throughput experiments","volume":"28","author":"Leek","year":"2012","journal-title":"Bioinformatics"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/12\/6\/1487\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:36:26Z","timestamp":1760175386000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/12\/6\/1487"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,6,7]]},"references-count":32,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2020,6]]}},"alternative-id":["cancers12061487"],"URL":"https:\/\/doi.org\/10.3390\/cancers12061487","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,6,7]]}}}