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

Abstract

Mutations in theCEBPA 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/EBP ), termed p30. While initial reports proposed that p30 represents a dominant-negative version of the wild-type C/EBP 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/EBP 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.

The clinical characteristics and prognosis of cytogenetically normal AML with single mutations of CEBPA

“…Consistent with previous researches, frameshift mutations were the main mutation type in N‐terminal, as in‐frame mutations in the C‐terminal in our study 9 . We also analyzed that CEBPAsm and CEBPAdm had no statistically difference in mutation types and the distribution of mutation regions, and the different distribution of mutant regions in the CEBPAsm group had similar effects on OS.…”

“…The N-terminal frameshift mutations caused the amino acid sequence frame drift, which will lead to the production of truncated nonfunctional protein or increasing expression of the negatively dominant isoform P30 protein, and the increase in P30 protein antagonized the full-length CEBPA protein function and cannot induce granulocyte differentiation. [9][10][11] C-terminal in-frame mutations affected DNA binding capacity or dimerization of the leucine zipper region. 12,13 Although it did not cause a dominant-negative effect, it could lead to the loss of CEBPA protein function.…”

Laboratory evaluation and prognostication among adults and children with CEBPA‐mutant acute myeloid leukemia

“…CEBPA is a single‐exon gene located on chromosome 19.q13.1 that encodes for CCAAT/enhancer‐binding protein‐α, a lineage‐specific basic leucine zipper (bZIP) transcription factor required to form myeloid progenitors from multipotent hematopoietic stem cells. The mRNA may be translated into either a full‐length 42‐kDA isoform (p42) or a truncated 30‐kDa (p30) isoform, both of which can homo‐ or hetero‐dimerize with other CEBP proteins to regulate genes involved in cell differentiation, survival, metabolism, growth, and inflammation 12,13 . The CEBPA protein contains two transactivation domains (TADs) at its N‐terminus as well as a basic leucine zipper at the C‐terminus that is responsible for DNA binding and dimerization.…”

“…In AML with biallelic CEBPA mutations, patients most often harbor an N‐terminus mutation on one allele and a C‐terminus mutation on the other allele, resulting in biallelic expression of aberrant p30 isoforms that cooperate to inhibit myeloid differentiation in a dominant‐negative manner via inhibition of the remaining p42 protein 18 . Recent findings by Schmidt and colleagues suggest that the truncated p30 isoform may act as a gain‐of‐function allele as well 13 . In animal studies, selective knockout of p42 in mice with preserved p30 expression leads to AML formation with complete penetrance 19 ; however, mice with knockout of both p42 and p30 expression failed to develop AML, further supporting the notion that residual function of the p30, rather than merely the lack of expression of the p42 isoform, contributes to leukemogenesis 20 …”

“…18 Recent findings by Schmidt and colleagues suggest that the truncated p30 isoform may act as a gain-of-function allele as well. 13 In animal studies, selective knockout of p42 in mice with preserved p30 expression leads to AML formation with complete penetrance 19 ; however, mice with knockout of both p42 and p30 expression failed to develop AML, further supporting the notion that residual function of the p30, rather than merely the lack of expression of the p42 isoform, contributes to leukemogenesis. 20 The 2016 revision to the WHO classification of myeloid neoplasms includes two distinct CEBPA-related disease entities: AML with biallelic mutations of CEBPA and AML with germline CEBPA mutation.…”