HISTONE DEACETYLASE ASSOCIATED WITH MSIN3A MEDIATES REPRESSION BY THEACUTE PROMYELOCYTIC LEUKEMIA-ASSOCIATED PLZF PROTEIN

The PLZF gene was identified first by its fusion with the retinoic aci d receptor alpha gene in the t(11;17) translocation associated with a retinoic acid resistant form of acute promyelocytic leukemia (APL). It encodes a kruppel-like zinc finger protein with a POZ domain shared w ith a subset of regulatory proteins including the BCL6 leukemogenic pr otein. PLZF, like BCL6, strongly represses transcription initiated fro m different promoters. Here we show that PLZF associates in vitro and in vivo with the Mad co-repressor mSin3A and the histone deacetylase H DAC1. Two domains in PLZF and the PAH1 structure of mSin3A mediate the se interactions. Trichostatin A, a specific inhibitor of histone deace tylases, significantly reduces PLZF repression. These data strongly su ggest that, like nuclear receptors and Mad, PLZF represses transcripti on by recruiting a histone deacetylase through the SMRT-mSin3-HDAC co- repressor complex. We also show that BCL6 associates with HDAC1 indica ting that this type of regulation might be common to POZ/Zinc finger p roteins involved in human leukemias. This work supports a role far der egulated histone deacetylation in the development of both lymphoid and myeloid neoplasia in human and suggests that targeted histone deacety lase inhibitors may be useful for treatment of certain types of malign ancies.