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Molecular and Cellular Biology, December 2004, p. 10456-10469, Vol. 24, No. 23
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.23.10456-10469.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Disruption of PLZP in Mice Leads to Increased T-Lymphocyte Proliferation, Cytokine Production, and Altered Hematopoietic Stem Cell Homeostasis

Francesco Piazza, José A. Costoya, Taha Merghoub, Robin M. Hobbs, and Pier Paolo Pandolfi^*

Cancer Biology and Genetics Program and Department of Pathology, Memorial Sloan-Kettering Cancer Center, Sloan-Kettering Division, Weill Graduate School of Medical Sciences, Cornell University, New York, New York

Received 8 July 2004/ Returned for modification 19 August 2004/ Accepted 1 September 2004

Deregulated function of members of the POK (POZ and Krüppel) family of transcriptional repressors, such as promyelocytic leukemia zinc finger (PLZF) and B-cell lymphoma 6 (BCL-6), plays a critical role in the pathogenesis of acute promyelocytic leukemia (APL) and non-Hodgkin's lymphoma, respectively. PLZP, also known as TZFP, FAZF, or ROG, is a novel POK protein that displays strong homology with PLZF and has been implicated in the pathogenesis of the cancer-predisposing syndrome, Fanconi's anemia, and of APL, in view of its ability to heterodimerize with the FANC-C and PLZF proteins, respectively. Here we report the generation and characterization of mice in which we have specifically inactivated the PLZP gene through in-frame insertion of a lacZ reporter and without perturbing the expression of the neighboring MLL2 gene. We show that PLZP-deficient mice display defects in cell cycle control and cytokine production in the T-cell compartment. Importantly, PLZP inactivation perturbs the homeostasis of the hematopoietic stem and/or progenitor cell. On the basis of our data, a deregulation of PLZP function in Fanconi's anemia and APL may affect the biology of the hematopoietic stem cell, in turn contributing to the pathogenesis of these disorders.

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* Corresponding author. Mailing address: Cancer Biology and Genetics Program and Department of Pathology, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, Box 110, 1275 York Ave., New York, NY 10021. Phone: (212) 639-6168. Fax: (212) 717-3102. E-mail: p_pandolfi{at}ski.mskcc.org.

Present address: Department of Clinical and Experimental Medicine, Clinical Immunology-Hematology Branch and Venetian Institute of Molecular Medicine, University of Padua, Padua, Italy.

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Molecular and Cellular Biology, December 2004, p. 10456-10469, Vol. 24, No. 23
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.23.10456-10469.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

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