The promyelocytic leukemia zinc finger (PLZF) protein is transcription factor, highly expressed in hematopoietic progenitor cells, that is fused to the retinoic acid receptor-a (RAR a) in t(11;17)-associated acute promyelocytic leukemia (APL). The t(11;17) APL is a distinct syndrome which, unlike the more common t(15;17) APL is unresponsive to retinoic acid or chemotherapy. PLZF-RARa which is generated in t(11;17) APL is an aberrant retinoid receptor which like the PML-RARa fusion of t(15;17) was a dominant negative inhibitor of wild-type RARa. Hence a common mechanism in leukemogenesis is disruption of retinoic acid signaling. The fusion of RARa to the PLZF may select for an aggressive clinical phenotype due to the disruption of the important function of PLZF in normal myeloid development. PLZF is a sequence specific DNA-binding transcriptional repressor and a growth suppressor inducing G1/S arrest and programmed cell death in myeloid cells. The PLZF protein contains an evolutionarily conserved motif called a POZ (poxvirus zinc finger) domain, found in other zinc finger proteins implicated in neoplasia, development and differentiation. The POZ domain appears to be necessary for PLZF protein to dimerize and repress gene transcription and for the transcriptional and biological effects of PLZF and the PLZF-RARa chimera. The mode of action and molecular target proteins of the POZ domains are unknown. The proposed research will: 1. Determine of how PLZF controls myeloid cell growth and differentiation by elucidation of PLZF target genes which bind the PLZF protein in vitro and in vivo such as IL-6, cyclin A and other to be identified by whole genome PCR. 2. Define how an evolutionarily conserved protein motif, the POZ domain, functions in transcriptional regulation, though mutagenesis of conserved residues and identification of partner proteins using the yeast two hybrid system. 3. Define protein-protein interaction networks that play a role in normal myelopoiesis and leukemogenesis (PML-PLZF, N-Cor-PLZF). 4. Extend knowledge of gene regulation in early hematopoiesis through characterization of the cis-acting sequences controlling expression of PLZF.
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