C/EBPα, the protein encoded by CEBPA, plays important roles in lineage determination and gene activation in a variety of cell types by activating transcription from lineage-specific promoters. In hematopoiesis, C/EBPα drives granulocytic differentiation of myelocytic cells. C/EBPα is also a key factor for hepatocyte and adipocyte development. A truncated form (30 kDa) is frequently observed. Both isoforms can be detected within the cell and it is likely that the ratio of isoforms is important in mediating proliferation and differentiation control.
Germline mutations in CEBPA have been described in 2 familial cases of acute myeloid leukemia (AML).
A number of different somatic mutations in CEBPA have been detected. They tend to cluster to two regions. The first group affects the N-terminal region of C/EBPα. These mutations are often insertions or deletions which cause frameshifts leading to premature truncation of the protein. In this case, translation is reinitiated at an internal ATG and the 30kDa protein, which lacks the first transactivating domain, is produced.
Secondly, in-frame or missense mutations occur within the C-terminal region of C/EBPα, disrupting the basic zipper region and thus affecting DNA binding, protein interactions as well as homo and heterodimerization with other C/EBP family members.
Mutations in CEBPA occur in approximately 10% of all AML and are associated with normal karyotype AML. These mutations tend to confer favorable prognosis. The involvement of CEBPA mutations in familial cases of AML, along with evidence of mutations persisting between presentation and relapse indicate that mutations in CEBPA are an early event in leukemogenesis.
In rare cases, AML has been found to be mutated in myelodysplasic syndromes (MDS), lung tumors and prostate tumors.
A t(14;19)(q32;q13) translocation leading to the IGH@-CEBPA fusion has been rarely observed in B-cell precursor acute lymphoblastic leukemia (BCP-ALL)
References (open access):
Complexity of CEBPA dysregulation in human acute myeloid leukemia. Pabst T, Mueller BU. Clin Cancer Res. 2009 Sep 1;15(17):5303-7.
An evolutionarily conserved PTEN-C/EBPalpha-CTNNA1 axis controls myeloid development and transformation. Fu CT, Zhu KY, Mi JQ, Liu YF, Murray ST, Fu YF, Ren CG, Dong ZW, Liu YJ, Dong M, Jin Y, Chen Y, Deng M, Zhang W, Chen B, Breslin P, Chen SJ, Chen Z, Becker MW, Zhu J, Zhang JW, Liu TX. Blood. 2010 Jun 10;115(23):4715-24