Repressible transgenic model of NRAS oncogene-driven mast cell disease in the mouse

Stephen M Wiesner, Jamie M. Jones, Diane E. Hasz, David A Largaespada

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1054-1062
Number of pages9
JournalBlood
Volume106
Issue number3
DOIs
StatePublished - Aug 1 2005

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Mastocytosis
Oncogenes
Mast-Cell Leukemia
Systemic Mastocytosis
Tetracycline
Transgenes
Mast Cells
Transgenic Mice
Animals
Thymus
Genetically Modified Animals
Trans-Activators
Doxycycline
Drinking Water
Liver
Thymus Gland
Skin
Bone
Spleen
Tissue

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Repressible transgenic model of NRAS oncogene-driven mast cell disease in the mouse. / Wiesner, Stephen M; Jones, Jamie M.; Hasz, Diane E.; Largaespada, David A.

In: Blood, Vol. 106, No. 3, 01.08.2005, p. 1054-1062.

Research output: Contribution to journalArticle

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