Mutant 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 mutant AML, we performed microscale, in vivo chromatin immunoprecipitation sequencing and identifi...

Full description

Saved in:
Bibliographic Details
Published in:Science advances 2019-07, Vol.5 (7), p.eaaw4304-eaaw4304
Main Authors: Jakobsen, Janus S, Laursen, Linea G, Schuster, Mikkel B, Pundhir, Sachin, Schoof, Erwin, Ge, Ying, d'Altri, Teresa, Vitting-Seerup, Kristoffer, Rapin, Nicolas, Gentil, Coline, Jendholm, Johan, Theilgaard-Mönch, Kim, Reckzeh, Kristian, Bullinger, Lars, Döhner, Konstanze, Hokland, Peter, Fitzgibbon, Jude, Porse, Bo T
Format: Article
Language:English
Subjects:
5'-Nucleotidase - genetics
Animals
Binding Sites
Cancer
CCAAT-Enhancer-Binding Proteins - genetics
CCAAT-Enhancer-Binding Proteins - metabolism
Enhancer Elements, Genetic
Epigenesis, Genetic
Gene Expression Profiling
Gene Expression Regulation, Leukemic
GPI-Linked Proteins - genetics
Humans
Leukemia, Myeloid, Acute - genetics
Leukemia, Myeloid, Acute - metabolism
Leukemia, Myeloid, Acute - mortality
Leukemia, Myeloid, Acute - pathology
Mice
Mutation
Nucleotide Motifs
Prognosis
Promoter Regions, Genetic
Protein Binding
Protein Isoforms - genetics
SciAdv r-articles
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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 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 mutant AML and the corresponding mouse model, we identified , 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.
ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.aaw4304