{
    "abstract": "To date, only one subtype of acute myeloid leukemia (AML), acute promyelocytic leukemia (APL) can be effectively treated by differentiation therapy utilizing all-trans retinoic acid (ATRA). Non-APL AMLs are resistant to ATRA. Here we demonstrate that the acetyltransferase GCN5 contributes to ATRA resistance in non-APL AML via aberrant acetylation of histone 3 lysine 9 (H3K9ac) residues maintaining the expression of stemness and leukemia associated genes. We show that inhibition of GCN5 unlocks an ATRA-driven therapeutic response. This response is potentiated by coinhibition of the lysine demethylase LSD1, leading to differentiation in most non-APL AML. Induction of differentiation was not correlated to a specific AML subtype, cytogenetic, or mutational status. Our study shows a previously uncharacterized role of GCN5 in maintaining the immature state of leukemic blasts and identifies GCN5 as a therapeutic target in AML. The high efficacy of the combined epigenetic treatment with GCN5 and LSD1 inhibitors may enable the use of ATRA for differentiation therapy of non-APL AML. Furthermore, it supports a strategy of combined targeting of epigenetic factors to improve treatment, a concept potentially applicable for a broad range of malignancies.",
    "authors": [
        {
            "affiliation": "Department of Hematology/Oncology, Clinic of Internal Medicine II, Jena University Hospital, Jena, Germany.\nInstitute of Molecular Cell Biology, Center for Molecular Biomedicine Jena (CMB), Jena University Hospital, Jena, Germany.",
            "firstname": "Melanie",
            "initials": "M",
            "lastname": "Kahl"
        },
        {
            "affiliation": "Department of Hematology/Oncology, Clinic of Internal Medicine II, Jena University Hospital, Jena, Germany.\nElse-Kr\u00f6ner-Forschungskolleg, Jena, Germany.",
            "firstname": "Annamaria",
            "initials": "A",
            "lastname": "Brioli"
        },
        {
            "affiliation": "Leibniz-Institute on Aging, Fritz-Lipmann-Institute, Jena, Germany.",
            "firstname": "Martin",
            "initials": "M",
            "lastname": "Bens"
        },
        {
            "affiliation": "Department of Hematology/Oncology, Clinic of Internal Medicine II, Jena University Hospital, Jena, Germany.\nLeibniz-Institute on Aging, Fritz-Lipmann-Institute, Jena, Germany.\nDepartment of Pediatric Oncology, Dana-Farber Cancer Institute and Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.",
            "firstname": "Florian",
            "initials": "F",
            "lastname": "Perner"
        },
        {
            "affiliation": "Leibniz-Institute on Aging, Fritz-Lipmann-Institute, Jena, Germany.",
            "firstname": "Anne",
            "initials": "A",
            "lastname": "Kresinsky"
        },
        {
            "affiliation": "Department of Hematology/Oncology, Clinic of Internal Medicine II, Jena University Hospital, Jena, Germany.",
            "firstname": "Ulf",
            "initials": "U",
            "lastname": "Schnetzke"
        },
        {
            "affiliation": "Department of Hematology/Oncology, Clinic of Internal Medicine II, Jena University Hospital, Jena, Germany.",
            "firstname": "Anna",
            "initials": "A",
            "lastname": "Hinze"
        },
        {
            "affiliation": "Department of Medical Biology, Medical University-Plovdiv, Plovdiv, Bulgaria.",
            "firstname": "Yordan",
            "initials": "Y",
            "lastname": "Sbirkov"
        },
        {
            "affiliation": "Department of Internal Medicine IV, Jena University Hospital, Jena, Germany.",
            "firstname": "Sven",
            "initials": "S",
            "lastname": "Stengel"
        },
        {
            "affiliation": "Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.",
            "firstname": "Giorgia",
            "initials": "G",
            "lastname": "Simonetti"
        },
        {
            "affiliation": "Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.\nDepartment of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.",
            "firstname": "Giovanni",
            "initials": "G",
            "lastname": "Martinelli"
        },
        {
            "affiliation": "School of Natural Sciences, University of Stirling, Stirling, UK.",
            "firstname": "Kevin",
            "initials": "K",
            "lastname": "Petrie"
        },
        {
            "affiliation": "Millitary Institute of Hygiene and Epidemiology, Warsaw, Poland.",
            "firstname": "Arthur",
            "initials": "A",
            "lastname": "Zelent"
        },
        {
            "affiliation": "Institute of Molecular Cell Biology, Center for Molecular Biomedicine Jena (CMB), Jena University Hospital, Jena, Germany.",
            "firstname": "Frank-Dietmar",
            "initials": "FD",
            "lastname": "B\u00f6hmer"
        },
        {
            "affiliation": "Leibniz-Institute on Aging, Fritz-Lipmann-Institute, Jena, Germany.",
            "firstname": "Marco",
            "initials": "M",
            "lastname": "Groth"
        },
        {
            "affiliation": "Department of Hematology/Oncology, Clinic of Internal Medicine II, Jena University Hospital, Jena, Germany.",
            "firstname": "Thomas",
            "initials": "T",
            "lastname": "Ernst"
        },
        {
            "affiliation": "Department of Hematology/Oncology, Clinic of Internal Medicine II, Jena University Hospital, Jena, Germany.\nLeibniz-Institute on Aging, Fritz-Lipmann-Institute, Jena, Germany.",
            "firstname": "Florian H",
            "initials": "FH",
            "lastname": "Heidel"
        },
        {
            "affiliation": "Department of Hematology/Oncology, Clinic of Internal Medicine II, Jena University Hospital, Jena, Germany.",
            "firstname": "Sebastian",
            "initials": "S",
            "lastname": "Scholl"
        },
        {
            "affiliation": "Department of Hematology/Oncology, Clinic of Internal Medicine II, Jena University Hospital, Jena, Germany.",
            "firstname": "Andreas",
            "initials": "A",
            "lastname": "Hochhaus"
        },
        {
            "affiliation": "Department of Hematology/Oncology, Clinic of Internal Medicine II, Jena University Hospital, Jena, Germany. tino.schenk@med.uni-jena.de.\nInstitute of Molecular Cell Biology, Center for Molecular Biomedicine Jena (CMB), Jena University Hospital, Jena, Germany. tino.schenk@med.uni-jena.de.",
            "firstname": "Tino",
            "initials": "T",
            "lastname": "Schenk"
        }
    ],
    "conclusions": null,
    "copyrights": null,
    "doi": "10.1038/s41375-019-0581-y\n10.1056/NEJMra1406184\n10.1056/NEJMoa1300874\n10.1038/nrc.2017.103\n10.1038/bjc.2014.412\n10.1074/mcp.R800013-MCP200\n10.1182/blood-2007-05-088344\n10.1038/nm.2661\n10.3324/haematol.2018.199190\n10.1182/blood-2017-09-807024\n10.1016/j.ccr.2012.03.014\n10.1074/jbc.274.9.5895\n10.1371/journal.pone.0054896\n10.1016/j.celrep.2016.09.079\n10.1038/nature07517\n10.1200/JCO.2009.23.4732\n10.1093/nar/gkv1101\n10.1002/anie.200453879\n10.1182/blood.V71.1.242.242\n10.1177/1010428317716629\n10.1016/j.cell.2011.07.032\n10.1172/JCI31861\n10.1038/s41467-017-01464-w\n10.1038/cddis.2012.151\n10.1016/j.cell.2016.03.015\n10.1016/j.cels.2017.03.005\n10.1016/j.celrep.2016.05.094\n10.1073/pnas.0503405102\n10.1038/sj.leu.2404401\n10.1038/nm.2415\n10.1158/1078-0432.CCR-04-1816\n10.1182/blood-2009-08-238899\n10.1084/jem.20150736\n10.1038/nature04020\n10.1126/science.1147674\n10.1038/ncomms10968\n10.1016/j.celrep.2018.03.012\n10.1038/scibx.2012.352\n10.4155/fmc-2017-0068",
    "journal": "Leukemia",
    "keywords": [],
    "methods": null,
    "publication_date": "2019-10-03",
    "pubmed_id": "31576004\n29456714",
    "results": null,
    "title": "The acetyltransferase GCN5 maintains ATRA-resistance in non-APL AML.",
    "xml": "<Element 'PubmedArticle' at 0x7885046b7600>"
}