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.
journal_name
Bloodjournal_title
Bloodauthors
Gerbaulet A,Wickenhauser C,Scholten J,Peschke K,Drube S,Horny HP,Kamradt T,Naumann R,Müller W,Krieg T,Waskow C,Hartmann K,Roers Adoi
10.1182/blood-2008-11-189605subject
Has Abstractpub_date
2011-02-10 00:00:00pages
2012-21issue
6eissn
0006-4971issn
1528-0020pii
blood-2008-11-189605journal_volume
117pub_type
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