The key myeloid transcription factor (TF) CEBPA is frequently mutated in acute myeloid leukemia (AML), but the molecular ramifications of this leukemic driver mutation remain elusive. To investigate CEBPA mutant AML, we compared gene expression changes in human CEBPA mutant AML and in the corresponding CebpaLp30 mouse model, and identified a conserved cross-species transcriptional program. ChIP-seq revealed aberrantly activated enhancers, exclusively occupied by the leukemia-associated CEBPA-p30 isoform. One leukemic-enhancer upstream of Nt5e, encoding CD73, was physically and functionally linked to this conserved AML gene, and could be activated by CEBPA. Targeting of CD73-adenosine signaling increased AML survival in transplanted mice. Our data indicate a first-in-class link between a TF cancer driver mutation and a druggable, direct transcriptional target.