Transcriptional deregulation is a central event in the development of acute myeloid leukemia (AML). To identify potential disturbances in gene regulation, we conducted an unbiased screen of allele-specific expression (ASE) in 209 AML cases. The gene encoding GATA binding protein 2 (GATA2) displayed ASE more often than any other myeloid- or cancer-related gene. GATA2ASE was strongly associated with CEBPAdouble mutations (DMs), with 95% of cases presenting GATA2ASE. In CEBPADM AML with GATA2mutations, the mutated allele was preferentially expressed. We found that GATA2ASE was a somatic event lost in complete remission, supporting the notion that it plays a role in CEBPADM AML. Acquisition of GATA2ASE involved silencing of 1 allele via promoter methylation and concurrent overactivation of the other allele, thereby preserving expression levels. Notably, promoter methylation was also lost in remission along with GATA2ASE. In summary, we propose that GATA2ASE is acquired by epigenetic mechanisms and is a prerequisite for the development of AML with CEBPADMs. This finding constitutes a novel example of an epigenetic hit cooperating with a genetic hit in the pathogenesis of AML.