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

Authors


  • Author contributions: S.D.: conception and design, collection of data and analysis and interpretation, and manuscript writing; B.B.: conception and design and manuscript writing; Y.Y.: collection and assembly of data; C.Y.P.: design, data analysis, and interpretation; M.A.S.M.: design, data analysis, and interpretation and manuscript writing; P.B.: conception and design, data analysis and interpretation, manuscript writing, financial support, and final approval of manuscript.

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

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