KIT receptor gain-of-function in hematopoiesis enhances stem cell self-renewal and promotes progenitor cell expansion Journal Article

Authors: Deshpande, S.; Bosbach, B.; Yozgat, Y.; Park, C. Y.; Moore, M. A. S.; Besmer, P.
Article 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 KitV558Δ and Kit T669I (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 KitV558D;T669I/1 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 Kit V558Δ;T669I/+ mice. Importantly, HSC from KitV558D;T669I/1 BM had a competitive advantage over wild-type HSC. In response to 5-fluorouracil treatment, elevated numbers of dividing Lin2Sca1 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. © AlphaMed Press.
Keywords: signal transduction; controlled study; splenectomy; fluorouracil; nonhuman; flow cytometry; animal cell; mouse; animal tissue; gastrointestinal stromal tumor; imatinib; stem cell factor receptor; bone marrow; erythroid precursor cell; spleen; animal experiment; animal model; stem cell; blood; hematopoietic stem cells; hematopoiesis; fetus; hematopoietic stem cell; self-renewal; polycythemia vera; hematocrit; stem cell expansion; erythrocytosis; fetus liver; gain of function mutation; erythroid progenitors
Journal Title: Stem Cells
Volume: 31
Issue: 8
ISSN: 1066-5099
Publisher: AlphaMed Press  
Date Published: 2013-08-01
Start Page: 1683
End Page: 1695
Language: English
DOI: 10.1002/stem.1419
PROVIDER: scopus
PMCID: PMC3775897
PUBMED: 23681919
Notes: --- - "Export Date: 1 October 2013" - "CODEN: STCEE" - "Source: Scopus"
Citation Impact
MSK Authors
  1. Christopher Yongchul Park
    89 Park
  2. Malcolm A S Moore
    527 Moore
  3. Peter Besmer
    114 Besmer
  4. Yasemin Yozgat
    4 Yozgat
  5. Benedikt Bosbach
    10 Bosbach
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