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Mast cell hyperplasia, B-cell malignancy, and intestinal inflammation in mice with conditional expression of a constitutively active kit

Gerbaulet, Alexander and Wickenhauser, Claudia and Scholten, Julia and Peschke, Katrin and Drube, Sebastian and Horny, Hans-Peter and Kamradt, Thomas and Naumann, Ronald and Müller, Werner and Krieg, Thomas and Waskow, Claudia and Hartmann, Karin and Roers, Axel. (2011) Mast cell hyperplasia, B-cell malignancy, and intestinal inflammation in mice with conditional expression of a constitutively active kit. Blood, 117 (6). pp. 2012-2021.

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Official URL: https://edoc.unibas.ch/70812/

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Abstract

Signaling through the receptor tyrosine kinase kit controls proliferation and differentiation of hematopoietic precursor cells and mast cells. Somatic point mutations of the receptor that constitutively activate kit signaling are associated with mastocytosis and various hematopoietic malignancies. We generated a Cre/loxP-based bacterial artificial chromosome transgenic mouse model that allows conditional expression of a kit gene carrying the kitD814V mutation (the murine homolog of the most common mutation in human mastocytosis, kitD816V) driven by the kit promoter. Expression of the mutant kit in cells of adult mice, including hematopoietic precursors, caused severe mastocytosis with 100% penetrance at young age frequently associated with additional hematopoietic (mostly B lineage-derived) neoplasms and focal colitis. Restriction of transgene expression to mature mast cells resulted in a similar mast cell disease developing with slower kinetics. Embryonic expression led to a hyperproliferative dysregulation of the erythroid lineage with a high rate of perinatal lethality. In addition, most adult animals developed colitis associated with mucosal mast cell accumulation. Our findings demonstrate that the effects of constitutive kit signaling critically depend on the developmental stage and the state of differentiation of the cell hit by the gain-of-function mutation.
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Allergy and Immunity (Hartmann)
UniBasel Contributors:Hartmann, Karin
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:American Society of Hematology
ISSN:0006-4971
e-ISSN:1528-0020
Note:Publication type according to Uni Basel Research Database: Journal article
Identification Number:
Last Modified:10 Nov 2020 16:12
Deposited On:10 Nov 2020 16:12

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