): Acute promyelocytic leukemia (APL) is defined as the accumulation of malignant promyelocytes in the bone marrow and peripheral blood and is generally associated with translocation (15;17). APL is unique amongst leukemias in its sensitivity to treatment with all-trans retinoic acid (ATRA). This group of investigators defined a second APL syndrome which does not respond to ATRA. These patients harbor an (11;17) reciprocal translocation which fuses RARalpha to a Kruppel-like zinc finger gene called PLZF (promyelocytic leukemia zinc finger). The structure of the PLZF protein is characterized by the presence of a conserved N-terminal protein-protein interaction sequence known as a POZ (poxvirus zinc finger) domain. The expression of PLZF is restricted to early myeloid cells and is quickly down-regulated as cells differentiate. The PLZF-RARalpha fusion protein behaves in a dominant negative manner by binding to RAR target genes and/or sequestering RXR. Concurrently, RARalpha-PLZF may activate genes normally repressed by PLZF. Also, the PLZF moiety may block RARalpha binding to transcription machinery or promoters. Mutational analysis of POZ domains suggests that the critical interface for protein-protein interaction is a hydrophobic face with coordinated charged residues. POZ domains mediate multimerization and may inhibit DNA binding. POZ proteins may also be involved in chromatin structure and interaction with the basal transcriptional machinery. The broad goals of the applicants are to understand the mechanisms of PLZF induced transcriptional regulation and how it exerts its actions through the evolutionarily conserved POZ domain. They hypothesize that PLZF is a transcription factor crucial for myeloid growth and development and that the POZ motif is necessary for this effect. Recent work from their lab suggests that PLZF is a growth suppressor, and that this function is disrupted in APL. PLZF binds specific DNA sequences upon which it mediates repression. The applicants will determine critical residues for self association, multimerization, transcriptional repression and nuclear speckle localization. They will assess whether the transcriptional repression and protein-protein interaction functions overlap and determine which proteins interact with PLZF via the POZ domain and are necessary for its function. They ultimately hope to demonstrate how these molecular events relate to myeloid growth and development and determine the characteristic phenotype of t(11;17) APL.
Showing the most recent 10 out of 11 publications
