ABERRANT RECRUITMENT OF THE NUCLEAR RECEPTOR COREPRESSOR-HISTONE DEACETYLASE COMPLEX BY THE ACUTE MYELOID-LEUKEMIA FUSION PARTNER ETO

Nuclear receptor corepressor (CoR)-histone deacetylase (HDAC) complex recruitment is indispensable for the biological activities of the reti noic acid receptor fusion proteins of acute promyelocytic leukemias. W e report here that ETO (eight-twenty-one or MTG8), which is fused to t he acute myelogenous leukemia 1 (AML1) transcription factor in t(8;21) AML, interacts via its zinc finger region with a conserved domain of the corepressors N-CoR and SMRT and recruits HDAC in vivo. The fusion protein AML1-ETO retains the ability of ETO to form stable complexes w ith N-CoR/SMRT and HDAC. Deletion of the ETO C terminus abolishes CoR binding and HDAC recruitment and severely impairs the ability of AML1- ETO to inhibit differentiation of hematopoietic precursors. These data indicate that formation of a stable complex with CoR-HDAC is crucial to the activation of the leukemogenic potential of AML1 by ETO and sug gest that aberrant recruitment of corepressor complexes is a general m echanism of leukemogenesis.