): 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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08CA073762-05
Application #
6376364
Study Section
Subcommittee G - Education (NCI)
Program Officer
Eckstein, David J
Project Start
1997-07-01
Project End
2002-06-30
Budget Start
2001-07-01
Budget End
2002-06-30
Support Year
5
Fiscal Year
2001
Total Cost
$90,720
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Melnick, Ari; Licht, Jonathan D (2002) Histone deacetylases as therapeutic targets in hematologic malignancies. Curr Opin Hematol 9:322-32
Melnick, Ari; Carlile, Graeme; Ahmad, K Farid et al. (2002) Critical residues within the BTB domain of PLZF and Bcl-6 modulate interaction with corepressors. Mol Cell Biol 22:1804-18
Zelent, A; Guidez, F; Melnick, A et al. (2001) Translocations of the RARalpha gene in acute promyelocytic leukemia. Oncogene 20:7186-203
Melnick, A; Ahmad, K F; Arai, S et al. (2000) In-depth mutational analysis of the promyelocytic leukemia zinc finger BTB/POZ domain reveals motifs and residues required for biological and transcriptional functions. Mol Cell Biol 20:6550-67
Melnick, A M; Westendorf, J J; Polinger, A et al. (2000) The ETO protein disrupted in t(8;21)-associated acute myeloid leukemia is a corepressor for the promyelocytic leukemia zinc finger protein. Mol Cell Biol 20:2075-86
Melnick, A; Carlile, G W; McConnell, M J et al. (2000) AML-1/ETO fusion protein is a dominant negative inhibitor of transcriptional repression by the promyelocytic leukemia zinc finger protein. Blood 96:3939-47
Ball, H J; Melnick, A; Shaknovich, R et al. (1999) The promyelocytic leukemia zinc finger (PLZF) protein binds DNA in a high molecular weight complex associated with cdc2 kinase. Nucleic Acids Res 27:4106-13
Hoatlin, M E; Zhi, Y; Ball, H et al. (1999) A novel BTB/POZ transcriptional repressor protein interacts with the Fanconi anemia group C protein and PLZF. Blood 94:3737-47
Melnick, A; Licht, J D (1999) Deconstructing a disease: RARalpha, its fusion partners, and their roles in the pathogenesis of acute promyelocytic leukemia. Blood 93:3167-215
Melnick, A; Fruchtman, S; Zelent, A et al. (1999) Identification of novel chromosomal rearrangements in acute myelogenous leukemia involving loci on chromosome 2p23, 15q22 and 17q21. Leukemia 13:1534-8

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