{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Jakobsen JS"],"funding":["Dansk Kræftforsknings Fond","Kræftens Bekæmpelse","Medical Research Council","The Danish Cancer Society","Novo Nordisk Foundation Section for Basic Stem Cell Biology","Novo Nordisk Fonden"],"pagination":["eaaw4304"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC6620102"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["5(7)"],"pubmed_abstract":["The key myeloid transcription factor (TF), CEBPA, is frequently mutated in acute myeloid leukemia (AML), but the direct molecular effects of this leukemic driver mutation remain elusive. To investigate <i>CEBPA</i> mutant AML, we performed microscale, in vivo chromatin immunoprecipitation sequencing and identified a set of aberrantly activated enhancers, exclusively occupied by the leukemia-associated CEBPA-p30 isoform. Comparing gene expression changes in human <i>CEBPA</i> mutant AML and the corresponding <i>Cebpa</i> <sup>Lp30</sup> mouse model, we identified <i>Nt5e</i>, encoding CD73, as a cross-species AML gene with an upstream leukemic enhancer physically and functionally linked to the gene. Increased expression of CD73, mediated by the CEBPA-p30 isoform, sustained leukemic growth via the CD73/A2AR axis. Notably, targeting of this pathway enhanced survival of AML-transplanted mice. Our data thus indicate a first-in-class link between a cancer driver mutation in a TF and a druggable, direct transcriptional target."],"journal":["Science advances"],"pubmed_title":["Mutant CEBPA directly drives the expression of the targetable tumor-promoting factor CD73 in AML."],"pmcid":["PMC6620102"],"funding_grant_id":["N/A","Theilgaard-Mønch group NNF","NNF17CC0027852","Porse group","R72-A4572","NNF12OC1015986","G0700052"],"pubmed_authors":["Pundhir S","Schoof E","Theilgaard-Monch K","Vitting-Seerup K","Reckzeh K","Bullinger L","Hokland P","Schuster MB","d'Altri T","Dohner K","Porse BT","Jendholm J","Rapin N","Fitzgibbon J","Ge Y","Jakobsen JS","Laursen LG","Gentil C"],"additional_accession":[]},"is_claimable":false,"name":"Mutant CEBPA directly drives the expression of the targetable tumor-promoting factor CD73 in AML.","description":"The key myeloid transcription factor (TF), CEBPA, is frequently mutated in acute myeloid leukemia (AML), but the direct molecular effects of this leukemic driver mutation remain elusive. To investigate <i>CEBPA</i> mutant AML, we performed microscale, in vivo chromatin immunoprecipitation sequencing and identified a set of aberrantly activated enhancers, exclusively occupied by the leukemia-associated CEBPA-p30 isoform. Comparing gene expression changes in human <i>CEBPA</i> mutant AML and the corresponding <i>Cebpa</i> <sup>Lp30</sup> mouse model, we identified <i>Nt5e</i>, encoding CD73, as a cross-species AML gene with an upstream leukemic enhancer physically and functionally linked to the gene. Increased expression of CD73, mediated by the CEBPA-p30 isoform, sustained leukemic growth via the CD73/A2AR axis. Notably, targeting of this pathway enhanced survival of AML-transplanted mice. Our data thus indicate a first-in-class link between a cancer driver mutation in a TF and a druggable, direct transcriptional target.","dates":{"release":"2019-01-01T00:00:00Z","publication":"2019 Jul","modification":"2025-04-20T03:25:50.888Z","creation":"2019-07-25T07:07:30Z"},"accession":"S-EPMC6620102","cross_references":{"pubmed":["31309149"],"doi":["10.1126/sciadv.aaw4304"]}}