Aberrant Recruitment of the Nuclear Receptor Corepressor-Histone Deacetylase Complex by the Acute Myeloid Leukemia Fusion Partner ETO

ABSTRACT

Nuclear receptor corepressor (CoR)-histone deacetylase (HDAC) complex recruitment is indispensable for the biological activities of the retinoic acid receptor fusion proteins of acute promyelocytic leukemias. We report here that ETO (eight-twenty-one or MTG8), which is fused to the 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 with 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 suggest that aberrant recruitment of corepressor complexes is a general mechanism of leukemogenesis.

ACKNOWLEDGMENTS

We thank C. Matteucci for excellent technical help, S. Nimer for the AML1/ETO cDNA, C. Hassig and S. Schreiber for HDAC1 antiserum, and C. Seiser for reagents and helpful discussions. V.G. and J.Z. contributed equally to this work.

This work was supported by NIH grants DK43806 and DK45586 (to M.A.L.), by the DNA Sequencing Core of the Center for Molecular Studies in Digestive and Liver Disease (NIH P30 DK50306) at the University of Pennsylvania, and by grants from AIRC and EC (Biomed program) to S.M. and P.G.P. M.F. is the recipient of a fellowship from INT (Milan).