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Effect of mast cell growth factor (c-kit ligand) on clonogenic leukemic precursor cells
H M Goselink1, D E Williams, W E Fibbe
1Department of Hematology, University Medical Center, Leiden, The Netherlands.
Abstract:
Mast cell growth factor (MGF), the ligand for the c-kit receptor, has been shown to be a hematopoietic growth factor that preferentially stimulates the proliferation of immature hematopoietic progenitor cells (HPC). We studied the effect of MGF on the in vitro growth of clonogenic leukemic precursor cells in the presence or absence of interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), and/or erythropoietin (EPO). Leukemic blood and bone marrow cells from patients with various types of acute myeloid leukemia (AML), chronic myeloid leukemia (CML) in chronic phase, as well as bone marrow samples from patients with myelodysplastic syndromes (MDS) were studied. MGF as a single factor did not induce significant colony formation by clonogenic leukemic precursor cells. In the presence of IL-3 and/or GM-CSF, MGF weakly stimulated the colony formation by clonogenic precursor cells from patients with AML. In contrast, in the presence of IL-3 and/or GM-CSF, MGF strongly induced both size and number of leukemic colonies from patients with CML in chronic phase. Furthermore, in the presence of EPO, MGF strongly stimulated erythroid colony formation by CML precursor cells. Cytogenetic analysis of the colonies showed that all metaphases after 1 week of culture were derived from the leukemic clone. In patients with MDS, MGF strongly stimulated myeloid colony formation in the presence of IL-3 and/or GM-CSF (up to fourfold), and erythroid colony formation in the presence of EPO (up to eightfold). Not only the number, but also the size of the colonies increased. In the presence of MGF, the percentage of normal metaphases increased in three patients tested after 1 week of culture compared with the initial suspension, suggesting that the normal HPC were preferentially stimulated compared with the preleukemic precursor cells. In the absence of exogenous EPO and in the presence of 10% human AB serum, MGF in the presence of IL-3 and/or GM-CSF induced erythroid colony formation from normal bone marrow and patients with MDS or CML, illustrating that MGF greatly diminished the EPO requirement for erythroid differentiation. These results indicate that MGF may be a candidate as a hematopoietic growth factor to stimulate normal hematopoiesis in patients with acute myeloid leukemia, or with myelodysplastic syndromes.
Insights
Mast cell growth factor (MGF) stimulates normal hematopoietic progenitor cells (HPC) and shows potential for treating myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). MGF enhances myeloid and erythroid colony formation, even reducing EPO dependence.
Area of Science:
- Hematology
- Molecular Biology
- Cancer Research
Background:
- Mast cell growth factor (MGF), also known as stem cell factor (SCF), is a key ligand for the c-kit receptor.
- MGF is recognized as a hematopoietic growth factor that preferentially stimulates immature hematopoietic progenitor cells (HPC).
- Its role in the proliferation of leukemic precursor cells requires further investigation, particularly in conjunction with other cytokines.
Purpose of the Study:
- To investigate the in vitro effect of MGF on clonogenic leukemic precursor cells from patients with myeloid malignancies.
- To assess MGF's impact on colony formation in the presence of interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), and/or erythropoietin (EPO).
- To determine MGF's potential as a therapeutic agent for stimulating normal hematopoiesis in AML and MDS.
Main Methods:
- Leukemic blood and bone marrow cells from patients with AML, CML (chronic phase), and MDS were cultured in vitro.
- Cells were treated with MGF alone or in combination with IL-3, GM-CSF, and/or EPO.
- Colony formation, size, and cytogenetic analysis of derived cells were evaluated.
Main Results:
- MGF alone did not induce significant colony formation.
- In combination with IL-3/GM-CSF, MGF weakly stimulated AML precursor colony formation but strongly enhanced CML colony number and size.
- MGF significantly stimulated myeloid colony formation in MDS patients (up to fourfold) and erythroid colony formation with EPO (up to eightfold), also increasing colony size.
- MGF diminished the EPO requirement for erythroid differentiation, inducing erythroid colonies even without exogenous EPO.
- MGF preferentially stimulated normal HPC, indicated by an increased percentage of normal metaphases in cultures from some patients.
Conclusions:
- MGF demonstrates significant synergistic effects with other cytokines in stimulating leukemic and normal hematopoietic progenitor cells.
- MGF shows strong potential for promoting myeloid and erythroid differentiation in MDS and CML.
- MGF may serve as a therapeutic candidate for stimulating normal hematopoiesis in patients with AML and MDS.