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

Roger Mulet-Lazaro, Stanley van Herk, Claudia Erpelinck, Eric Bindels, Mathijs A Sanders, Carlo Vermeulen, Ivo Renkens, Peter Valk, Ari M Melnick, Jeroen de Ridder, Michael Rehli, Claudia Gebhard, Ruud Delwel, Bas J Wouters*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

10 Citations (Scopus)


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 (DMs), 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 was 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 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 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 DMs. This finding constitutes a novel example of an epigenetic hit cooperating with a genetic hit in the pathogenesis of AML.

Original languageEnglish
Pages (from-to)160-177
Number of pages18
Issue number2
Publication statusPublished - 15 Jul 2021

Bibliographical note

This work was supported by grants and fellowships from the Dutch
Cancer Society (R.D., B.J.W., R.M.-L., and S.v.H.) and a Leukemia &
Lymphoma Society (LLS) Special Fellowship Award (B.J.W.). A.M.M. is
supported by National Institutes of Health, National Cancer Institute
grants UG1 CA233332 and R01 CA198089, and LLS Specialized Center
of Research grant 7013-17.

© 2021 by The American Society of Hematology.


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