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Keywords:

  • Erythroid progenitors;
  • Hematopoietic stem cells;
  • Self-renewal;
  • Signal transduction

Abstract

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 KitV558Δ and KitT669I (human KITT670I) mutations found in imatinib-resistant GIST. The KitV558Δ;T669I/+ 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 KitV558Δ;T669I/+ mice normalized upon splenectomy. In accordance with increased erythroid progenitors, myeloerythroid progenitor numbers were also elevated in the KitV558Δ;T669I/+ mice. Hematopoietic stem cell (HSC) numbers in the bone marrow (BM) of KitV558Δ;T669I/+ mice were unchanged in comparison to wild-type mice. However, increased HSC numbers were observed in fetal livers and the spleen and peripheral blood of adult KitV558Δ;T669I/+ mice. Importantly, HSC from KitV558Δ;T669I/+ BM had a competitive advantage over wild-type HSC. In response to 5-fluorouracil treatment, elevated numbers of dividing LinSca+ cells were found in the KitV558Δ;T669I/+ BM compared to wild type. Our study demonstrates that signaling from the KitV558Δ;T669I/+ receptor has important consequences in hematopoiesis enhancing HSC self-renewal and resulting in increased erythropoiesis. STEM Cells 2013;31:1683- -1695