Disruption of PLZP in mice leads to increased T-lymphocyte proliferation, cytokine production, and altered hematopoietic stem cell homeostasis.
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.
Piazza
Francesco
F
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.
Costoya
José A
JA
Merghoub
Taha
T
Hobbs
Robin M
RM
Pandolfi
Pier Paolo
PP
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
D017252:CD3 Complex; D016207:Cytokines; D012097:Repressor Proteins; C406863:Rog protein, mouse; D012260:Ribonucleases