C/EBPα dysregulation in AML and ALL

Abstract

The transcription factor CCAAT/enhancer binding protein a (C/EBPα) is a critical regulator of myeloid development, directing granulocyte, and monocyte differentiation. As such, it is dysregulated in more than half of patients with acute myeloid leukemia (AML). C/EBPα expression is suppressed as result of common leukemia-associated genetic and epigenetic alterations such as AML1-ETO, BCR-ABL, FLT3-ITD, or CEBPA promoter methylation. In addition, 10-15% of patients with AML with intermediate risk cytogenetics are characterized by mutations of the CEBPA gene. Two classes of mutations are described. N-terminal changes result in expression of a truncated dominant negative C/EBPαp30 isoform. C-terminal mutations are in-frame insertions or deletions resulting in alteration of the leucine zipper preventing dimerization and DNA binding. Often, patients carry both N- and C-terminal mutations each affecting a different allele, and a mouse model recapitulates the human phenotype. Patients with mutated CEBPA AML comprise a clinically distinct group with favorable outcome consistently seen in patients with biallelic mutations. In addition, C/EBP family members are aberrantly expressing from the immunoglobulin heavy chain locus in 2% of pre-B ALLs. This review summarizes the normal hematopoietic developmental pathways regulated by C/EBPα and discusses the molecular pathways involved in mutated CEBPA AML and ALL.

Figure 1

Diagram depicting C/EBPαp42, truncated C/EBPαp30, and the location of C/EBPαLZ in-frame insertions and deletions. BR, basic region; LZ, leucine zipper; TAD, trans-activation domain.

Figure 2

Model for the transcriptional control of myeloid development by RUNX1, C/EBPα, and PU.1. RUNX1 stimulates transcription of the genes encoding C/EBPα and PU.1, and C/EBPα also activates the PU.1 gene. C/EBPα then hetero-dimerizes with AP-1 proteins and cooperates with PU.1 to favor monopoiesis, whereas C/EBPα homo-dimers cooperate with NF-κB p50 to favor granulopoiesis.