Allele-specific expression of GATA2 due to epigenetic dysregulation in CEBPA double-mutant AML. Academic Article uri icon

Overview

abstract

  • 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.

publication date

  • July 15, 2021

Research

keywords

  • Alleles
  • CCAAT-Enhancer-Binding Proteins
  • Epigenesis, Genetic
  • GATA2 Transcription Factor
  • Gene Expression Regulation, Leukemic
  • Leukemia, Myeloid, Acute
  • Mutation

Identity

PubMed Central ID

  • PMC8489178

Scopus Document Identifier

  • 85110071415

Digital Object Identifier (DOI)

  • 10.1182/blood.2020009244

PubMed ID

  • 33831168

Additional Document Info

volume

  • 138

issue

  • 2