The promyelocytic leukemia zinc finger (PLZF) protein is a transcription factor, expressed in hematopoietic progenitor cells, fused to the retinoic acid receptor-alpha (RAR alpha) in t(11;17)-associated acute promyelocytic leukemia (APL). Over the past 9 years, through two periods of funding, our group characterized t(11;17) APL as a distinct syndrome, unresponsive to retinoic acid. We determined that the PLZF-RARalpha fusion generated in t(11;17) is a dominant negative form of PAR that actively recruits corepressors and histone deacteylase molecules to RAR target genes. The study of the PLZF fusion protein helped solidify the model of aberrant transcriptional repression as a pathogenic basis of leukemia. Though progress has been gratifying, many questions remain. The nature of the critical target genes of the retinoid receptor blocked by the fusion proteins of APL is not certain. The way in which genes are repressed is incompletely understood. Histone deacetylases are critically involved but other modes of chromatin modification, chromatin remodeling and epigenetic silencing of repressed genes are likely. The PLZF protein represses through a number of co-repressors attracted though the BTB/POZ Domain. Further structure of this domain will yield further insights and potential therapeutic modalties in the disease. APL in animal models occurs after a considerable delay, indicating that other mutations are required for the disease to occur. One such cooperating mutation may be the mutation of the fit3 receptor tyrosine kinase molecule. One mode of cooperation may be the ability of the APL fusion proteins to abrogate the p53 pathway and prevent premature cellular senescence in response to activation of ras/map kinasse pathways. PML is a modulator of p53 function and PLZF may be as well. 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 mutagensis 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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA059936-13
Application #
6848339
Study Section
Special Emphasis Panel (ZRG1-CPA (02))
Program Officer
Mufson, R Allan
Project Start
1993-04-01
Project End
2008-01-31
Budget Start
2005-02-07
Budget End
2006-01-31
Support Year
13
Fiscal Year
2005
Total Cost
$390,258
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
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Licht, Jonathan D (2009) Acute promyelocytic leukemia--weapons of mass differentiation. N Engl J Med 360:928-30
Doulatov, Sergei; Notta, Faiyaz; Rice, Kim L et al. (2009) PLZF is a regulator of homeostatic and cytokine-induced myeloid development. Genes Dev 23:2076-87
Buzzai, Monica; Licht, Jonathan D (2008) New molecular concepts and targets in acute myeloid leukemia. Curr Opin Hematol 15:82-7
Polo, Jose M; Ci, Weimin; Licht, Jonathan D et al. (2008) Reversible disruption of BCL6 repression complexes by CD40 signaling in normal and malignant B cells. Blood 112:644-51
Petrie, K; Guidez, F; Zhu, J et al. (2008) Retinoblastoma protein and the leukemia-associated PLZF transcription factor interact to repress target gene promoters. Oncogene 27:5260-6
Denne, Miriam; Sauter, Marlies; Armbruester, Vivienne et al. (2007) Physical and functional interactions of human endogenous retrovirus proteins Np9 and rec with the promyelocytic leukemia zinc finger protein. J Virol 81:5607-16
Rice, K L; Hormaeche, I; Licht, J D (2007) Epigenetic regulation of normal and malignant hematopoiesis. Oncogene 26:6697-714
Guidez, Fabien; Howell, Louise; Isalan, Mark et al. (2005) Histone acetyltransferase activity of p300 is required for transcriptional repression by the promyelocytic leukemia zinc finger protein. Mol Cell Biol 25:5552-66
Melnick, Ari M; Adelson, Kerin; Licht, Jonathan D (2005) The theoretical basis of transcriptional therapy of cancer: can it be put into practice? J Clin Oncol 23:3957-70

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