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Circulating megakaryocyte progenitors in myeloproliferative disorders are hypersensitive to interleukin-3
S Kobayashi1, M Teramura, S Hoshino
1Department of Haematology, Tokyo Women's Medical College, Japan.
Abstract:
Previous studies have reported that megakaryocyte progenitors in myeloproliferative disorders (MPD) formed spontaneous megakaryocyte colonies without the addition of megakaryocyte colony-stimulating factor (Meg-CSF). To determine whether this spontaneous colony formation is due to autocrine proliferation of MPD megakaryocyte progenitors or to hypersensitivity to Meg-CSF that might exist in the culture system, we investigated colony-forming unit-megakaryocytes (CFU-Meg) in the peripheral blood of 11 MPD patients, using serum-free cultures. Spontaneous megakaryocyte colonies were observed in serum-free cultures of nonadherent mononuclear cells (NAdMNC) obtained from MPD patients with thrombocytosis, whereas the NAdMNC of MPD patients without thrombocytosis, that of patients with reactive thrombocytosis and normal subjects never formed spontaneous colonies. However, the spontaneous colonies from MPD patients with thrombocytosis disappeared in cultures using highly purified CD34-positive cells as target cells. To study the hypersensitivity of megakaryocyte progenitors to Meg-CSF, dose-response experiments were performed with interleukin-3 (IL-3). CFU-Meg from MPD patients with thrombocytosis showed maximal growth at the concentrations of IL-3 lower than those for normal subjects. CFU-Meg of MPD patients without thrombocytosis and that of patients with reactive thrombocytosis showed the same colony growth response to IL-3 as that of normal subjects. This result indicates that the CFU-Meg of MPD patients with thrombocytosis are hypersensitive to IL-3. It also suggests that spontaneous colony formation by NAdMNC is not due to the autocrine growth of megakaryocyte progenitors but is due to the hypersensitivity of megakaryocyte progenitors to Meg-CSF, such as IL-3, released by accessory cells. Furthermore, it is possible that such hypersensitivity of CFU-Meg to IL-3 might be a pathogenic factor in MPD with accompanying thrombocytosis.
Insights
Myeloproliferative disorders (MPD) with thrombocytosis show spontaneous megakaryocyte colony formation due to hypersensitivity to growth factors like IL-3, not autocrine proliferation. This hypersensitivity may be a key factor in MPD pathogenesis.
Area of Science:
- Hematology
- Oncology
- Cell Biology
Background:
- Megakaryocyte progenitors in myeloproliferative disorders (MPD) can form colonies without added growth factors.
- The mechanism behind this spontaneous colony formation requires clarification.
Purpose of the Study:
- To investigate the cause of spontaneous megakaryocyte colony formation in MPD patients.
- To determine if MPD megakaryocyte progenitors exhibit hypersensitivity to megakaryocyte colony-stimulating factor (Meg-CSF).
Main Methods:
- Serum-free cultures of peripheral blood mononuclear cells (NAdMNC) from MPD patients and controls.
- Analysis of colony-forming unit-megakaryocytes (CFU-Meg) formation.
- Dose-response experiments with interleukin-3 (IL-3) on purified CD34-positive cells.
Main Results:
- Spontaneous megakaryocyte colonies formed from MPD patients with thrombocytosis but not from those without or controls.
- Spontaneous colonies disappeared when using purified CD34-positive cells.
- CFU-Meg from MPD patients with thrombocytosis showed maximal growth at lower IL-3 concentrations, indicating hypersensitivity.
Conclusions:
- Spontaneous colony formation in MPD is due to hypersensitivity of megakaryocyte progenitors to growth factors like IL-3, not autocrine proliferation.
- Hypersensitivity of CFU-Meg to IL-3 may be a pathogenic factor in MPD with thrombocytosis.