Oncogenic mechanisms of C/EBPα deregulation in myeloid malignancies. (A) Transcriptional deregulation: (i) promoter DNA methylation silences CEBPA ; and (ii) oncogenic transcription regulators (eg, AML1-ETO or EVI1) bind to CEBPA enhancer and downregulate mRNA expression. (B) Posttranscriptional deregulation: (i) the BCR-ABL oncoprotein upregulates an RNA-binding protein that destabilizes CEBPA transcripts; (ii) upregulation of microRNA-690 destabilizes CEBPA transcripts and alters granulocytic development. (C) Posttranslational deregulation: (i) an increase in tribbles pseudokinase 2 (TRIB2) levels degrades the CEBPA protein by the recruitment of COP1 ubiquitin ligase¹¹⁷ ; (ii) internal tandem duplication in the FLT3 receptor constitutively activates the signaling molecule ERK, which inhibits homodimerization of C/EBPα and, hence, interferes with its function by phosphorylation on serine 21.