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Updated: May 11, 2026
Pan-myeloid Differentiation of Human Cord Blood Derived CD34+ Hematopoietic Stem and Progenitor Cells
Published on: August 9, 2019
KIT receptor gain-of-function in hematopoiesis enhances stem cell self-renewal and promotes progenitor cell expansion
Shayu Deshpande1, Benedikt Bosbach, Yasemin Yozgat
1Developmental Biology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
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.
Insights
A new mouse model with imatinib-resistant gastrointestinal stromal tumor (GIST) mutations in Kit exhibits altered hematopoiesis. This model shows increased erythropoiesis and enhanced hematopoietic stem cell self-renewal, offering insights into GIST and blood cell development.
Area of Science:
- Hematology
- Oncology
- Molecular Biology
Background:
- The KIT receptor tyrosine kinase is crucial for hematopoiesis.
- Imatinib-resistant gastrointestinal stromal tumor (GIST) often involves KIT mutations.
- A novel mouse model was developed to study these mutations.
Purpose of the Study:
- To investigate the role of specific imatinib-resistant KIT mutations (Kit(V558Δ) and Kit(T669I)) in hematopoiesis.
- To characterize the resulting hematopoietic phenotype in a mouse model.
- To explore the impact on hematopoietic stem cell (HSC) function.
Main Methods:
- Generation of a mouse model with Kit(V558Δ;T669I/+) mutations.
- Phenotypic analysis including hematocrit, progenitor cell counts, and HSC numbers.
- Assessment of HSC competitive advantage and response to chemotherapy (5-fluorouracil).
- Splenectomy was performed to evaluate its effect on hematocrit.
Main Results:
- Kit(V558Δ;T669I/+) mice developed microcytic erythrocytosis and increased erythroid progenitors.
- Elevated myeloerythroid progenitor numbers were observed.
- HSC numbers increased in fetal liver, spleen, and peripheral blood, with enhanced self-renewal and competitive advantage.
- Increased erythrocytosis normalized after splenectomy.
Conclusions:
- Signaling through the Kit(V558Δ;T669I/+) receptor significantly impacts hematopoiesis.
- The mutations enhance HSC self-renewal and promote erythropoiesis.
- This model provides valuable insights into the mechanisms of imatinib-resistant GIST and aberrant hematopoiesis.
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