Generation of a novel knock-in mouse line expressing oncogenic Kit D814V in the hematopoietic stem cell compartment as a preclinical model for systemic mastocytosis.

Research in mastocytosis, characterized by clonal expansion of mast cells (MC), and driven by the KIT D816V mutation in >90% of patients, has been hampered by the lack of in vivo models. Here, we describe a novel knock-in mouse line expressing Kit D814V (murine homolog to human KIT D816V) in the hematopoietic compartment by Scl-CreER-mediated recombination. Scl-Cre;KitD814V fl/+ mice presented increased MC progenitors in the bone marrow (BM) leading to MC expansion in the skin, stomach, spleen and liver, and increased serum levels of murine MC protease-1 (mMCP-1) and mMCP-6. Additionally, mice exhibited a myeloid neoplasm with leukocytosis, erythrocytosis, extramedullary hematopoiesis, and hepatosplenomegaly. In competitive BM transplantation, Kit D814V cells had a proliferative advantage over wild-type cells, resulting in increased MC, leukocytosis, erythrocytosis, and extramedullary hematopoiesis in recipient mice. Treatment of transplanted mice with a KIT-targeting tyrosine kinase inhibitor was able to control the mutant clone, and led to significant reduction of skin MC, leukocytes as well as reticulocytes, and normalization of spleen weight. In conclusion, we describe here a novel mouse model presenting a phenotype closely resembling human systemic mastocytosis with associated hematologic neoplasm (SM-AHN), which could help in clarifying the pathogenesis of mastocytosis and exploring novel therapeutic strategies.