AML1-ETO Downregulates the Granulocytic Differentiation Factor C/EBPalpha in t(8;21) Myeloid Leukemia

Nat Med. 2001 Apr;7(4):444-51. doi: 10.1038/86515.

Abstract

The transcription factor CCAAT/enhancer binding protein alpha, or C/EBPalpha, encoded by the CEBPA gene, is crucial for the differentiation of granulocytes. Conditional expression of C/EBPalpha triggers neutrophilic differentiation, and Cebpa knockout mice exhibit an early block in maturation. Dominant-negative mutations of CEBPA have been found in some patients with acute myeloid leukemia (AML), but not in AML with the t(8;21) translocation which gives rise to the fusion gene RUNX1-CBF2T1 (also known as AML1-ETO) encoding the AML1-ETO fusion protein. RUNX1-CBF2T1 positive-AML blasts had eight-fold lower CEBPA RNA levels and undetectable C/EBPalpha protein levels compared with other subgroups of AML patients. Conditional expression of RUNX1-CBF2T1 in U937 cells downregulated CEBPA mRNA, protein and DNA binding activity. AML1-ETO appears to suppress C/EBPalpha expression indirectly by inhibiting positive autoregulation of the CEBPA promoter. Conditional expression of C/EBPalpha in AML1-ETO-positive Kasumi-1 cells results in neutrophilic differentiation. We suggest that restoring C/EBPalpha expression will have therapeutic implications in RUNX1-CBF2T1-positive leukemias.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Base Sequence
  • CCAAT-Enhancer-Binding Protein-alpha / genetics*
  • Cell Differentiation / genetics
  • Chromosomes, Human, Pair 21 / genetics
  • Chromosomes, Human, Pair 8 / genetics
  • Core Binding Factor Alpha 2 Subunit
  • DNA Primers / genetics
  • DNA-Binding Proteins / genetics
  • Down-Regulation
  • Humans
  • Leukemia, Myeloid, Acute / genetics*
  • Leukemia, Myeloid, Acute / pathology
  • Mice
  • Oncogene Proteins, Fusion / genetics
  • Oncogene Proteins, Fusion / physiology*
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA, Neoplasm / genetics
  • RNA, Neoplasm / metabolism
  • RUNX1 Translocation Partner 1 Protein
  • Transcription Factors / genetics
  • Transcription Factors / physiology*
  • Translocation, Genetic

Substances

  • AML1-ETO fusion protein, human
  • CCAAT-Enhancer-Binding Protein-alpha
  • Core Binding Factor Alpha 2 Subunit
  • DNA Primers
  • DNA-Binding Proteins
  • Oncogene Proteins, Fusion
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • RNA, Neoplasm
  • RUNX1 Translocation Partner 1 Protein
  • RUNX1 protein, human
  • Runx1 protein, mouse
  • Transcription Factors