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

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 lineagederived) neoplasms and focal colitis. Restriction of transgene expression to mature mast cells resulted in a similar mast cell disease developing with slower IntroductionMast cells are best known for their effector function in type I allergic responses 1,2 but were recently shown to be important initiators and effectors also of innate immunity as well as modulators of adaptive immune responses. 3,4 Differentiation and homeostasis of mast cells are dependent on signaling through the transmembrane receptor tyrosine kinase kit, the receptor for stem cell factor (SCF). 5,6 In addition, mast cell migration and several proinflammatory mast cell functions are regulated by SCF-kit signaling. 7 The kit gene is a proto-oncogene that was originally discovered as the cellular homolog (c-kit) of the feline sarcoma virus oncogene v-kit. 8 Binding of SCF to the kit receptor activates various signaling cascades, including the phosphoinositide 3-kinases, protein kinase C, mitogen-activated protein kinase, and janus kinase/signal transducers and activators of transcription pathways to control hematopoiesis, lymphopoiesis, and gametogenesis. 9 The human disease mastocytosis is characterized by abnormal numbers of mast cells accumulating in skin and/or various other organs. The patients may have inadequate release of mast cell mediators causing anaphylactoid symptoms with potentially fatal outcome. The condition is associated with gain-of-function mutations of kit, which result in uncontrolled autophosphorylation of the kit receptor with ligand-independent, constitutive signaling. [10][11][12][13] The majority of mastocytosis patients carry one particular activating point mutation in exon 17 (D816V). 10,14 The kitD816V protein was shown to enhance the proliferation of human cells in vitro and to transform murine cells in vivo under certain conditions that allow proper processing of the protein despite the cross-species situation. 15 Clinical manifestations of mastocytosis associated with the kitD816V gain-of-function mutation can differ dramatically from patient to patient. 11,14,[16][17][18] In a disease subset designated "cutaneous mastocytosis," the abnormal mast cell accumulation is restricted to the skin. Cutaneous mastocytosis with onset in childho...

KIT D816V–mutated bone marrow mesenchymal stem cells in indolent systemic mastocytosis are associated with disease progression

“…Altogether, these results are consistent with recent observations in a mouse model with conditional expression of a constitutively active D814V-mutated KIT which showed a greater MC disease severity when the mutation was expressed in undifferentiated HPCs vs (only) more mature cells. 61 In addition, our findings might also contribute to explain why ISM patients with MC-restricted KIT mutation in the BM have a normal life expectancy and very rarely progress to more aggressive disease. 7 Of note, here, we reported a higher rate of progression of ISM patients than that observed in previous (large) series of ISM patients 7,54,62 ; this is probably due to the preferential selection of cases with multilineage involvement of hematopoiesis by the KIT D816V mutation vs MCrestricted KIT D816V mutation because the latter cases typically showed very low rates of disease progression 7 and/or a longer follow-up in this vs other previously reported series.…”

SH2 Domain-Containing Phosphatase 2 Is a Critical Regulator of Connective Tissue Mast Cell Survival and Homeostasis in Mice

“…Recently, new and improved models of inducible or constitutive mast cell deficiency were reported using Mcpt5-Cre mice crossed with simian diphtheria toxin transgenic mice (13). The Mcpt5-Cre system was also used to drive the expression of Kit D814V in mature mast cells, leading to mastocytosis in the skin that increased with age and progressed to mast cell tumors and skin lesions (18). Crossing these mice with shp2 fl/fl mice would allow for testing the role of SHP2 in mastocytosis in vivo.…”

Pak and Rac GTPases promote oncogenic KIT–induced neoplasms

“…The presence of this mutation in SM and AML is associated with poor prognosis and overall survival. In mice, the expression of this mutation is sufficient to recapitulate several cardinal features of human SM (4). This mutation changes the conformation of the KIT receptor, resulting in altered substrate recognition and constitutive tyrosine autophosphorylation, which leads to a constitutive ligand-independent growth (5-7) that is resistant to imatinib and shows little therapeutic efficacy in response to dasatinib in most SM patients (8,9).…”