THE T(8-21) FUSION PRODUCT, AML-1-ETO, ASSOCIATES WITH C EBP-ALPHA, INHIBITS C/EBP-ALPHA-DEPENDENT TRANSCRIPTION, AND BLOCKS GRANULOCYTIC DIFFERENTIATION/

Citation
Jj. Westendorf et al., THE T(8-21) FUSION PRODUCT, AML-1-ETO, ASSOCIATES WITH C EBP-ALPHA, INHIBITS C/EBP-ALPHA-DEPENDENT TRANSCRIPTION, AND BLOCKS GRANULOCYTIC DIFFERENTIATION/, Molecular and cellular biology, 18(1), 1998, pp. 322-333
Citations number
80
Categorie Soggetti
Biology,"Cell Biology
ISSN journal
02707306
Volume
18
Issue
1
Year of publication
1998
Pages
322 - 333
Database
ISI
SICI code
0270-7306(1998)18:1<322:TTFPAA>2.0.ZU;2-P
Abstract
AML-1B is a hematopoietic transcription factor that is functionally in activated by multiple chromosomal translocations in human acute myelob lastic and B-cell Lymphocytic leukemias. The t(8;21)(q22;q22) transloc ation 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 tra nscriptional activation. Here we demonstrate that AML-1-ETO also inhib its C/EBP-alpha-dependent activation of the myeloid cell-specific, rat defensin NP-3 promoter. AML-IB bound the core enhancer motifs present in the NP-3 promoter and activated transcription approximately sixfol d. 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 inhi bited C/EBP-alpha-dependent activity as well as the synergistic activa tion. In contrast, the inv(16) product, which indirectly targets AML f amily members by fusing their heterodimeric DNA binding partner, CBF-b eta, to the myosin heavy chain, inhibited AML-1B but not C/EBP-alpha a ctivation or the synergistic activation. AML-1-ETO and C/EBP-alpha wer e coimmunoprecipitated and thus physically interact in vivo. Deletion mutants demonstrated that the C terminus of ETO was required for AML-l -ETO-mediated repression of the synergistic activation but not for ass ociation with C/EBP-alpha. Finally, overexpression of AML-1-ETO in mye loid progenitor cells prevented granulocyte colony-stimulating factor- induced differentiation. Thus, AML-1-ETO may contribute to leukemogene sis by specifically inhibiting C/EBP-alpha- and AML-1B-dependent activ ation of myeloid promoters and blocking differentiation.