KIT Receptor Gain‐of‐Function in Hematopoiesis Enhances Stem Cell Self‐Renewal and Promotes Progenitor Cell Expansion

The KIT receptor tyrosine kinase has important roles in hematopoiesis. We have recently produced a mouse model for imatinib resistant gastrointestinal stromal tumor (GIST) carrying the Kit V558D and Kit T669I (human KIT T670I ) mutations found in imatinib-resistant GIST. The Kit V558D;T669I/1 mice developed microcytic erythrocytosis with an increase in erythroid progenitor numbers, a phenotype previously seen only in mouse models of polycythemia vera with alterations in Epo or Jak2. Significantly, the increased hematocrit observed in Kit V558D;T669I/1 mice normalized upon splenectomy. In accordance with increased erythroid progenitors, myeloerythroid progenitor numbers were also elevated in the Kit V558D;T669I/1 mice. Hematopoietic stem cell (HSC) numbers in the bone marrow (BM) of Kit V558D;T669I/1 mice were unchanged in