biostudies-literatureJakobsen JSDansk Kræftforsknings FondKræftens BekæmpelseMedical Research CouncilThe Danish Cancer SocietyNovo Nordisk Foundation Section for Basic Stem Cell BiologyNovo Nordisk Fondeneaaw4304https://www.ebi.ac.uk/biostudies/studies/S-EPMC6620102biostudies-literatureUnknown5(7)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> ^Lp30 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.Science advancesMutant CEBPA directly drives the expression of the targetable tumor-promoting factor CD73 in AML.PMC6620102N/ATheilgaard-Mønch group NNFNNF17CC0027852Porse groupR72-A4572NNF12OC1015986G0700052Pundhir SSchoof ETheilgaard-Monch KVitting-Seerup KReckzeh KBullinger LHokland PSchuster MBd'Altri TDohner KPorse BTJendholm JRapin NFitzgibbon JGe YJakobsen JSLaursen LGGentil CfalseMutant CEBPA directly drives the expression of the targetable tumor-promoting factor CD73 in AML.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> ^Lp30 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.2019-01-01T00:00:00Z2019 Jul2025-04-20T03:25:50.888Z2019-07-25T07:07:30ZS-EPMC66201023130914910.1126/sciadv.aaw4304