title: Disruption of PLZP in mice leads to increased T-lymphocyte proliferation, cytokine production, and altered hematopoietic stem cell homeostasis.
abstract: Deregulated function of members of the POK (POZ and Kruppel) 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.
authors.affiliation: 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, USA.
authors.forename: Francesco
authors.initials: F
authors.lastname: Piazza
authors.forename: José A
authors.initials: JA
authors.lastname: Costoya
authors.forename: Taha
authors.initials: T
authors.lastname: Merghoub
authors.forename: Robin M
authors.initials: RM
authors.lastname: Hobbs
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Pandolfi
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015152:Blotting, Northern; D017252:CD3 Complex / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D049109:Cell Proliferation; D002469:Cell Separation; D016207:Cytokines / Q000096:biosynthesis*; D005199:Fanconi Anemia / Q000235:genetics; D005434:Flow Cytometry; D017353:Gene Deletion; D017930:Genes, Reporter; D005838:Genotype; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D007150:Immunohistochemistry; D007763:Lac Operon; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008957:Models, Genetic; D008969:Molecular Sequence Data; D016296:Mutagenesis; D012097:Repressor Proteins / Q000235:genetics* / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012260:Ribonucleases / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology* / Q000378:metabolism; D013737:Testis / Q000378:metabolism; D019076:Transgenes
chemical_list: D017252:CD3 Complex; D016207:Cytokines; D012097:Repressor Proteins; C406863:Rog protein, mouse; D012260:Ribonucleases