Gain-of-Function Effects of N-Terminal CEBPA Mutations in Acute Myeloid Leukemia.

Luisa Schmidt,Florian Grebien,Elizabeth Heyes

doi:10.1002/bies.201900178

Abstract

Mutations in the CEBPA gene are present in 10–15% of acute myeloid leukemia (AML) patients. The most frequent type of mutations leads to the expression of an N-terminally truncated variant of the transcription factor CCAAT/enhancer-binding protein alpha (C/EBPα), termed p30. While initial reports proposed that p30 represents a dominant-negative version of the wild-type C/EBPα protein, other studies show that p30 retains the capacity to actively regulate gene expression. Recent global transcriptomic and epigenomic analyses have advanced the understanding of the distinct roles of the p30 isoform in leukemogenesis. This review outlines direct and indirect effects of the C/EBPα p30 variant on oncogenic transformation of hematopoietic progenitor cells and discusses how studies of N-terminal CEBPA mutations in AML can be extrapolated to identify novel gain-of-function features in oncoproteins that arise from recurrent truncating mutations in transcription factors.

Highlights

C/EBPα Isoforms and Their FunctionsThe transcription factor CCAAT/enhancer-binding protein alpha (C/EBPα) is necessary for the development of several structures, including liver, airway epithelium, and adipose tissue. [1,2] In the hematopoietic system, C/EBPα is important for stem and progenitor cell function and regulates the differentiation of myeloid cells.[3]
In addition to different distribution of transcription factor binding motifs, p42-bound regions were associated with lower histone 3 lysine 27 (H3K27) acetylation and lower histone 3 lysine 4 (H3K4) mono-methylation, while p30-bound regions as well as loci occupied by both p42 and p30 displayed high levels of these histone marks. As both H3K27 acetylation and H3K4 monomethylation are characteristics for enhancer regions, these results suggest that p30 preferably binds to primed enhancer regions, while p42 might be less dependent on the prior presence of chromatin marks that are associated with active transcription
These data demonstrate that the C/EBPα p30 protein represents a functional isoform of C/EBPα that can exert oncogenic effects through binding to enhancers and promoters and/or via preferential interaction with epigenetic modifiers and co-factors, which results in the specific regulation of p30-target genes

Summary

Introduction

The transcription factor CCAAT/enhancer-binding protein alpha (C/EBPα) is necessary for the development of several structures, including liver, airway epithelium, and adipose tissue. [1,2] In the hematopoietic system, C/EBPα is important for stem and progenitor cell function and regulates the differentiation of myeloid cells.[3]. CRISPR/ Cas9-mediated mutagenesis revealed that p30-expressing cells are dependent on a functional MLL1 protein.[47] Disruption of the MLL1 complex function by small-molecule-mediated inhibition of the MLL1-Menin or MLL1-WDR5 interaction resulted in impaired proliferation, induction of differentiation, and elevated levels of apoptosis of CEBPAmutated cells.[46,47] Taken together, these data demonstrate that the C/EBPα p30 protein represents a functional isoform of C/EBPα that can exert oncogenic effects through binding to enhancers and promoters and/or via preferential interaction with epigenetic modifiers and co-factors, which results in the specific regulation of p30-target genes

Truncating Transcription Factor Mutations in Leukemia-A Recurrent Theme

De-regulated Transcription Factor Activity Drives Oncogenic Transformation

Findings

Conclusion