C/EBPα in normal and malignant myelopoiesis

CCAAT/enhancer binding protein alpha (C/EBP alpha) dimerizes via its leucine zipper (LZ) domain to bind DNA via its basic region and activate transcription via N-terminal trans-activation domains. The activity of C/EBP alpha is modulated by several serine/threonine kinases and via sumoylation, its gene is activated by RUNX1 and additional transcription factors, its mRNA stability is modified by miRNAs, and its mRNA is subject to translation control that affects AUG selection. In addition to inducing differentiation, C/EBP alpha inhibits cell cycle progression and apoptosis. Within hematopoiesis, C/EBP alpha levels increase as long-term stem cells progress to granulocyte-monocyte progenitors (GMP). Absence of C/EBP alpha prevents GMP formation, and higher levels are required for granulopoiesis compared to monopoiesis. C/EBP alpha interacts with AP-1 proteins to bind hybrid DNA elements during monopoiesis, and induction of Gfi-1, C/EBP epsilon, KLF5, and miR-223 by C/EBP alpha enables granulopoiesis. The CEBPA ORF is mutated in approximately 10 % of acute myeloid leukemias (AML), leading to expression of N-terminally truncated C/EBP alpha p30 and C-terminal, in-frame C/EBP alpha LZ variants, which inhibit C/EBP alpha activities but also play additional roles during myeloid transformation. RUNX1 mutation, CEBPA promoter methylation, Trib1 or Trib2-mediated C/EBP alpha p42 degradation, and signaling pathways leading to C/EBP alpha serine 21 phosphorylation reduce C/EBP alpha expression or activity in additional AML cases.