Type of publication:
Type of document:
Heyes, E; Schmidt, L; Manhart, G; Eder, T; Proietti, L; Grebien, F
Identification of gene targets of mutant C/EBPα reveals a critical role for MSI2 in CEBPA-mutated AML.
Leukemia. 2021 35 (9) 2526-2538.
Authors Vetmeduni Vienna:
Heyes Elizabeth Claire
Vetmed Research Units
Institute for Medical Biochemistry
Common Oncogenic Mechanisms in Multi-Partner Translocation Families in Acute Myeloid Leukemia
ARCH - Age-Related Changes in Hematopoiesis
- Mutations in the gene encoding the transcription factor CCAAT/enhancer-binding protein alpha (C/EBPα) occur in 10-15% of acute myeloid leukemia (AML). Frameshifts in the CEBPA N-terminus resulting in exclusive expression of a truncated p30 isoform represent the most prevalent type of CEBPA mutations in AML. C/EBPα p30 interacts with the epigenetic machinery, but it is incompletely understood how p30-induced changes cause leukemogenesis. We hypothesized that critical effector genes in CEBPA-mutated AML are dependent on p30-mediated dysregulation of the epigenome. We mapped p30-associated regulatory elements (REs) by ATAC-seq and ChIP-seq in a myeloid progenitor cell model for p30-driven AML that enables inducible RNAi-mediated knockdown of p30. Concomitant p30-dependent changes in gene expression were measured by RNA-seq. Integrative analysis identified 117 p30-dependent REs associated with 33 strongly down-regulated genes upon p30-knockdown. CRISPR/Cas9-mediated mutational disruption of these genes revealed the RNA-binding protein MSI2 as a critical p30-target. MSI2 knockout in p30-driven murine AML cells and in the CEBPA-mutated human AML cell line KO-52 caused proliferation arrest and terminal myeloid differentiation, and delayed leukemia onset in vivo. In summary, this work presents a comprehensive dataset of p30-dependent effects on epigenetic regulation and gene expression and identifies MSI2 as an effector of the C/EBPα p30 oncoprotein.© 2021. The Author(s), under exclusive licence to Springer Nature Limited part of Springer Nature.