The t(8;21) fusion product, AML-1-ETO, associates with C/EBP-α, inhibits C/EBP-α-dependent transcription, and blocks granulocytic differentiation

Jennifer J. Westendorf, Cindy M. Yamamoto, Noel Lenny, James R. Downing, Michael E. Selsted, Scott W. Hiebert

Research output: Contribution to journalArticle

237 Scopus citations


AML-1B is a hematopoietic transcription factor that is functionally inactivated by multiple chromosomal translocations in human acute myeloblastic and B-cell lymphocytic leukemias. The t(8;21)(q22)q22) translocation replaces the C terminus, including the transactivation domain of AML-1B, with ETO, a nuclear protein of unknown function. We previously showed that AML-1-ETO is a dominant inhibitor of AML-1B-dependent transcriptional activation. Here we demonstrate that AML-1-ETO also inhibits C/EBP-α-dependent activation of the myeloid cell-specific, rat defensin NP- 3 promoter. AML-1B bound the core enhancer motifs present in the NP-3 promoter and activated transcription approximately sixfold. Similarly, C EBP- α bound NP-3 promoter sequences and activated transcription approximately sixfold. Coexpression of C/EBP-α with AML-1B or its family members, AML-2 and murine AML-3, synergistically activated the NP-3 promoter up to 60-fold. The t(8;21) product, AML-1-ETO, repressed AML-1B-dependent activation of NP- 3 and completely inhibited C/EBP-α-dependent activity as well as the synergistic activation. In contrast the inv(16) product, which indirectly targets AML family members by fusing their heterodimeric DNA binding partner, CBF-β, to the myosin heavy chain, inhibited AML-1B but not C/EBP-α activation or the synergistic activation. AML-1-ETO and C/EBP-α were coimmunoprecipitated and thus physically interact in vivo. Deletion mutants demonstrated that the C terminus of ETO was required for AML-1-ETO-mediated repression of the synergistic activation but not for association with C/EBP- α. Finally, overexpression of AML-1-ETO in myeloid progenitor cells prevented granulocyte colony-stimulating factor-induced differentiation. Thus, AML-1-ETO may contribute to leukemogenesis by specifically inhibiting C/EBP-α- and AML-1B-dependent activation of myeloid promoters and blocking differentiation.

Original languageEnglish (US)
Pages (from-to)322-333
Number of pages12
JournalMolecular and cellular biology
Issue number1
StatePublished - Jan 1998

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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