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Allele-specific expression of GATA2 due to epigenetic dysregulation in double mutated CEBPA AML

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. GATA2 ASE was strongly associated with CEBPA double mutations (CEBPA DM), with 95% of cases presenting GATA2 ASE. In CEBPA DM AML with GATA2 mutations, the mutated allele was preferentially expressed. We found that GATA2 ASE is a somatic event lost in complete remission, supporting the notion that it plays a role in CEBPA DM AML. Acquisition of GATA2 ASE involved silencing of one allele via promoter methylation, compensated by overactivation of the other allele, thereby preserving expression levels. Notably, promoter methylation was also lost in remission together with GATA2 ASE. In summary, we propose that GATA2 ASE is acquired by epigenetic mechanisms and is a prerequisite for the development of AML with CEBPA DM. This finding constitutes a novel example of an epigenetic hit cooperating with a genetic hit in the pathogenesis of AML.

Click on a Dataset ID in the table below to learn more, and to find out who to contact about access to these data

Dataset ID Description Technology Samples
EGAD00001007580 Illumina NovaSeq 6000 209
EGAD00001007581 Illumina NovaSeq 6000 209
EGAD00001007582 Illumina HiSeq 4000 72
EGAD00001007583 NextSeq 500 64
EGAD00001007645 Illumina NovaSeq 6000 12
EGAD00001007646 Illumina NovaSeq 6000 12
Publications Citations
The leukemic oncogene EVI1 hijacks a MYC super-enhancer by CTCF-facilitated loops.
Nat Commun 12: 2021 5679