Show simple item record

dc.contributor.authorGiotopoulos, Georgeen
dc.contributor.authorChan, W-Ien
dc.contributor.authorHorton, Sarahen
dc.contributor.authorRuau, Daviden
dc.contributor.authorGallipoli, Paoloen
dc.contributor.authorFowler, Aen
dc.contributor.authorCrawley, Cen
dc.contributor.authorPapaemmanuil, Een
dc.contributor.authorCampbell, PJen
dc.contributor.authorGottgens, Bertholden
dc.contributor.authorDeursen, JM Vanen
dc.contributor.authorCole, PAen
dc.contributor.authorHuntly, Brianen
dc.date.accessioned2015-05-18T09:01:04Z
dc.date.available2015-05-18T09:01:04Z
dc.date.issued2015-04-20en
dc.identifier.citationGiotopoulos et al. Oncogene (2016), 35(3), pp. 279–289. doi:10.1038/onc.2015.92en
dc.identifier.issn0950-9232
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/247742
dc.description.abstractGrowing evidence links abnormal epigenetic control to the development of hematological malignancies. Accordingly, inhibition of epigenetic regulators is emerging as a promising therapeutic strategy. The acetylation status of lysine residues in histone tails is one of a number of epigenetic post-translational modifications that alter DNA-templated processes, such as transcription, to facilitate malignant transformation. Although histone deacetylases are already being clinically targeted, the role of histone lysine acetyltransferases (KAT) in malignancy is less well characterized. We chose to study this question in the context of acute myeloid leukemia (AML), where, using in vitro and in vivo genetic ablation and knockdown experiments in murine models, we demonstrate a role for the epigenetic regulators CBP and p300 in the induction and maintenance of AML. Furthermore, using selective small molecule inhibitors of their lysine acetyltransferase activity, we validate CBP/p300 as therapeutic targets in vitro across a wide range of human AML subtypes. We proceed to show that growth retardation occurs through the induction of transcriptional changes that induce apoptosis and cell-cycle arrest in leukemia cells and finally demonstrate the efficacy of the KAT inhibitors in decreasing clonogenic growth of primary AML patient samples. Taken together, these data suggest that CBP/p300 are promising therapeutic targets across multiple subtypes in AML.
dc.description.sponsorshipFunding in the Huntly laboratory comes from Cancer Research UK, Leukemia Lymphoma Research, the Kay Kendal Leukemia Fund, the Leukemia lymphoma Society of America, the Wellcome Trust, The Medical Research Council and an NIHR Cambridge Biomedical Research Centre grant. Patient samples were processed in the Cambridge Blood and Stem Cell Biobank.
dc.languageEnglishen
dc.language.isoenen
dc.publisherNature Publishing Group
dc.subjectAMLen
dc.subjectepigenetic regulatorsen
dc.subjectsmall molecule inhibitorsen
dc.titleThe epigenetic regulators CBP and p300 facilitate leukemogenesis and represent therapeutic targets in Acute Myeloid Leukemiaen
dc.typeArticle
dc.description.versionThis is the author accepted manuscript. The final version is available via NPG at http://dx.doi.org/10.1038/onc.2015.92en
prism.endingPage289
prism.publicationDate2015en
prism.publicationNameOncogeneen
prism.startingPage279
prism.volume35en
dc.rioxxterms.funderCRUK
dc.rioxxterms.funderWellcome Trust
dc.rioxxterms.funderMRC
dc.rioxxterms.funderNIHR
dcterms.dateAccepted2015-02-05en
rioxxterms.versionofrecord10.1038/onc.2015.92en
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2015-04-20en
dc.contributor.orcidGiotopoulos, George [0000-0003-1390-6592]
dc.contributor.orcidGallipoli, Paolo [0000-0001-7254-2253]
dc.contributor.orcidGottgens, Berthold [0000-0001-6302-5705]
dc.contributor.orcidHuntly, Brian [0000-0003-0312-161X]
dc.identifier.eissn1476-5594
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idLeukaemia & Lymphoma Research (12029)
pubs.funder-project-idWellcome Trust (097922/Z/11/Z)
pubs.funder-project-idMRC (MC_PC_12009)
pubs.funder-project-idLeukemia & Lymphoma Society (7001-12)
pubs.funder-project-idCancer Research UK (12765)
pubs.funder-project-idBBSRC (BB/I00050X/1)
pubs.funder-project-idMedical Research Council (MR/M010392/1)
pubs.funder-project-idWorldwide Cancer Research (14-1069)
rioxxterms.freetoread.startdate2015-10-20


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record