Mutant CEBPA directly drives the expression of the targetable tumor-promoting factor CD73 in AML
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- Mutant CEBPA directly drives theexpression ofthetargetable tumor-promoting factor CD73 inA ML
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Janus S Jakobsen, Linea G Laursen, Mikkel B Schuster, Sachin Pundhir, Erwin Schoof, Ying Ge, Teresa d'Altri, Kristoffer Vitting-Seerup, Nicolas Rapin, Coline Gentil, Johan Jendholm, Kim Theilgaard-Mönch, Kristian Reckzeh, Lars Bullinger, Konstanze Döhner, Peter Hokland, Jude Fitzgibbon, Bo T Porse
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 CEBPA 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 CEBPA mutant AML and the corresponding CebpaLp30 mouse model, we identified Nt5e, 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.
|Number of pages||17|
|Publication status||Published - 2019|