To create a model in which to study the effects of RAS dysregulation in hematopoietic disease, we developed separate founder lines of transgenic mice, with the tetracycline transactivator (tTA) driven by the Vav hematopoietic promoter in one line and NRASV12 driven by the tetracycline responsive element (TRE2) in the other. When these lines are crossed, doubly transgenic animals uniformly develop a disease similar to human aggressive systemic mastocytosis (ASM) or mast cell leukemia (MCL) when they are between 2 and 4 months of age. Disease is characterized by tissue infiltrates of large, well-differentiated mast cells in the spleen, liver, skin, lung, and thymus. Analysis of bone sections shows small to large foci of similarly well-differentiated mast cells. Results also show that transgene expression and diseases are repressible through the administration of doxycycline in the drinking water of affected animals, indicating that NRASV12 expression is required to initiate and maintain disease in doubly transgenic mice. Our inducible system of transgenes, developed as a model of mutant NRASV12 oncogene-driven myeloid disease, will be useful for studying the role of RAS dysregulation in hematopoietic disease in general and in discrete human diseases, specifically ASM and MCL.