Growth-inhibiting activity of transcription factor C/EBPalpha, its role in haematopoiesis and its tumour suppressor or oncogenic properties in leukaemias.

The CCAAT/enhancer binding protein alpha (C/EBPalpha or CEBPA) is the founding member of a family of related leucine zipper transcription factors that play important roles in myeloid differentiation. Targeted inactivation of C/EBPalpha in mice demonstrates its importance in the proper development and function of liver, adipose tissue, lung and haematopoietic tissues. C/EBPalpha is highly expressed in these differentiated tissues where it controls differentiation-dependent gene expression and inhibits cell proliferation. Learning more about the precise molecular functions of the C/EBPalpha protein and how these are affected by leukaemogenic mutations should lead to an improved understanding of the cellular functions that are disrupted in patients with AML. Decreased expression of C/EBPalpha but not C/EBPalpha mutation has been shown in patients with granulocytic leukaemias that are associated with translocations t(8;21), inv (16) or t(15;17). Derived fusion proteins repress C/EBPalpha expression. Differentiation therapy of some AML types is based on restoring C/EBPalpha function. However, apparently normal C/EBPalpha is overexpressed in BCP-ALL harbouring the translocation t(14; 19)(q32; q13). C/EBPalpha may exhibit oncogenic as well as tumour suppressor properties in human leukaemogenesis. C/EBPalpha mutations were not found in non-haematopoietic cancers. DNA hypermethylation of the upstream C/EBPalpha promoter region is responsible for very low C/EBPalpha expression in human lung and endometrial cancer. C/EBPalpha expression may be a biomarker for early detection of these cancers and DNA-modifying drugs such as demethylating agents and/or histone deacetylase inhibitors could be used in the treatment of these malignancies.