The ability for siRNA containing lentiviral vectors to specifically downregulate gene expression in the hematopoietic system following hematopoietic stem cell transplantation provides a new tool for developing disease models of leukemia and other hematological disorders. The tumor suppressor gene, p53, has been implicated in the genesis or progression of hematological malignancies, such as AML, MDS, and CML, and disorders such as myeloproliferative disease (MPD). Following transduction of Ly5.1 hematopoietic stem cells using a lentiviral vector expressing small interfering RNAs specific for mouse p53, cells were transplanted into lethally irradiated syngeneic recipient mice. Peripheral blood analyses by FACS at 7 weeks posttransplant showed significantly increased numbers of Gr1 Mac1 double positive progenitor like cells in 4 of 4 mice (73±14% compared to control siGFP transplanted mice 5±0.5%). Interestingly, 3 of 4 transplanted mice showed signs of morbidity by 16 weeks posttransplant due to a myelogenous proliferative disease (MPD) phenotype characterized by high peripheral blood neutrophil counts (>70% of white blood cells) and anemia (<106 RBC/μL), and extensive neutrophil infiltration into spleen and liver. Furthermore, peripheral blood smears show an expansion of megakaryocytes. Bone marrow mononuclear cells from transplanted mice were analyzed for p53 protein expression following p53 stabilization by irradiation and significantly lower levels of p53 were detected in sip53-transduced mice compared to siGFP lentiviral vector control mice. No altering of normal hematopoietic cell differentiation was observed in control mice from nonspecific RNAi interactions, as determined by FACS or blood cell count analyses. These results demonstrate that downregulated expression of p53 in mice hematopoietic cells yields a myelogenous proliferative disease and creates a model for the study of p53 involvement in the genesis and progression of hematological disorders. Furthermore, these results demonstrate the ability of lentiviral vector mediated siRNA to efficiently downregulate endogenous gene expression in vivo and model human disease.