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

Westendorf JJ, Yamamoto CM, Lenny N, Downing JR, Selsted ME, Hiebert SW
Mol Cell Biol. 1998 18 (1): 322-33

PMID: 9418879 · PMCID: PMC121499 · DOI:10.1128/mcb.18.1.322

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-alpha-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-alpha bound NP-3 promoter sequences and activated transcription approximately sixfold. Coexpression of C/EBP-alpha 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-alpha-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-beta, to the myosin heavy chain, inhibited AML-1B but not C/EBP-alpha activation or the synergistic activation. AML-1-ETO and C/EBP-alpha 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-alpha. 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-alpha- and AML-1B-dependent activation of myeloid promoters and blocking differentiation.

MeSH Terms (22)

Animals CCAAT-Enhancer-Binding Proteins Cell Differentiation Chromosomes, Human, Pair 8 Chromosomes, Human, Pair 21 Core Binding Factor Alpha 2 Subunit COS Cells DNA-Binding Proteins Gene Expression Regulation, Neoplastic Granulocytes Hematopoiesis Humans Leukemia Nuclear Proteins Oncogene Proteins, Fusion Promoter Regions, Genetic Rats Recombinant Fusion Proteins RUNX1 Translocation Partner 1 Protein Transcription, Genetic Transcription Factors Translocation, Genetic

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