The ETO protein disrupted in t(8;21)-associated acute myeloid leukemia is a corepressor for the promyelocytic leukemia zinc finger protein

The ETO protein was originally identified by its fusion to the AML-1 transc ription factor in translocation (8;21) associated with the M2 form of acute myeloid leukemia (AML). The resulting AML-1-ETO fusion is an aberrant tran scriptional regulator due to the ability of ETO, which does not bind DNA it self, to recruit the transcriptional corepressors N-CoR, SMRT, and Sin3A an d histone deacetylases. The promyelocytic leukemia zinc finger (PLZF) prote in is a sequence-specific DNA-binding transcriptional factor fused to retin oic acid receptor cr in acute promyelocytic leukemia associated with the (1 1;17)(q23;q21) translocation. PLZF also mediates transcriptional repression through the actions of corepressors and histone deacetylases. We found tha t ETO is one of the corepressors recruited by PLZF. The PLZF and ETO protei ns associate in vivo and in vitro, and ETO can potentiate transcriptional r epression by PLZF. The N-terminal portion of ETO forms complexes with PLZF, while the C-terminal region, which was shown to bind to N-CoR and SMRT, is required for the ability of ETO to augment transcriptional repression by P LZF. The second repression domain (RD2) of PLZF, not the POZ/BTB domain, is necessary to bind to ETO. Corepression by ETO was completely abrogated by histone deacetylase inhibitors. This identifies ETO as a cofactor for a seq uence-specific transcription factor and indicates that, like other corepres sors, it functions through the action of histone deactylase.