title: KIT receptor gain-of-function in hematopoiesis enhances stem cell self-renewal and promotes progenitor cell expansion.
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 Kit(V558Δ) and Kit(T669I) (human KIT(T670I) ) mutations found in imatinib-resistant GIST. The Kit(V558Δ;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 Kit(V558Δ;T669I/+) mice normalized upon splenectomy. In accordance with increased erythroid progenitors, myeloerythroid progenitor numbers were also elevated in the Kit(V558Δ;T669I/+) mice. Hematopoietic stem cell (HSC) numbers in the bone marrow (BM) of Kit(V558Δ;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 Kit(V558Δ;T669I/+) mice. Importantly, HSC from Kit(V558Δ;T669I/+) BM had a competitive advantage over wild-type HSC. In response to 5-fluorouracil treatment, elevated numbers of dividing Lin(-) Sca(+) cells were found in the Kit(V558Δ;T669I/+) BM compared to wild type. Our study demonstrates that signaling from the Kit(V558Δ;T669I/+) receptor has important consequences in hematopoiesis enhancing HSC self-renewal and resulting in increased erythropoiesis.
authors.affiliation: Developmental Biology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Shayu
authors.initials: S
authors.lastname: Deshpande
authors.forename: Benedikt
authors.initials: B
authors.lastname: Bosbach
authors.forename: Yasemin
authors.initials: Y
authors.lastname: Yozgat
authors.forename: Christopher Y
authors.initials: CY
authors.lastname: Park
authors.forename: Malcolm A S
authors.initials: MA
authors.lastname: Moore
authors.forename: Peter
authors.initials: P
authors.lastname: Besmer
mesh_terms: D000818:Animals; D048708:Cell Growth Processes / Q000502:physiology; D004195:Disease Models, Animal; D041905:Erythroid Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D006410:Hematopoiesis / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D019009:Proto-Oncogene Proteins c-kit; D005472:Fluorouracil
keywords: Erythroid progenitors; Hematopoietic stem cells; Self-renewal; Signal transduction