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Abnormal modulation of granulocyte/macrophage progenitor proliferation by prostaglandin E in chronic
Abstract:
The effect of prostaglandin E1 (PGE1) on the in vitro proliferation of peripheral blood granulocyte/macrophage progenitors (CFUc) from the patients with chronic myeloproliferative disorders was examined. PGE1 was found to be a dose-dependent inhibitor of normal peripheral blood and bone marrow CFUc. Peripheral blood CFUc from patients with chronic myelogenous leukemia (CML) showed normal inhibition when cultured in the absence of exogenous colony stimulating factor (CSF). The addition of CSF to CML peripheral blood cultures resulted in complete abrogation of normal PGE1 inhibition. Dose-titration studies in which increasing amounts of CSF were added to CML cultures showed decreasing PGE1 inhibition with increasing CSF concentration. This observation indicated increased efficiency of competition between the colony stimulating effect of CSF and the colony inhibitory effect of PGE1 in CML. Peripheral blood CFUc from patients with myelofibrosis/myeloid metaplasia (MM) showed heterogeneous responses to PGE1 with complex dose-effect curves showing variable combinations of stimulation and inhibition of CFUc proliferation. Further studies showed that these effects of PGE1 were blocked by the prostaglandin antagonist SC-19220, and were not due to elaboration of CSF or non-CSF enhancers of CFUc proliferation from MM adherent cells. Cell fractionation studies in 2 patients, with MM showed dual populations of CFUc, one responding abnormally, and another normally to PGE1, accounting in part for the complex dose-response curves. These studies indicate that significant abnormalities exist in the in vitro response to PGE1 by CFUc from patients with chronic myeloproliferative disorders. Deficiencies in PGE 1 inhibition may contribute to the excess myelopoiesis seen in these disorders.
Insights
Prostaglandin E1 (PGE1) inhibits normal blood progenitors, but this effect is altered in chronic myeloproliferative disorders. Abnormal PGE1 responses in these patients may contribute to excessive blood cell production.
Area of Science:
- Hematology
- Cell Biology
- Oncology
Background:
- Prostaglandin E1 (PGE1) is known to affect cell proliferation.
- Chronic myeloproliferative disorders (MPDs) are characterized by the overproduction of blood cells.
- The role of PGE1 in the regulation of hematopoietic progenitors in MPDs is not fully understood.
Purpose of the Study:
- To investigate the effect of PGE1 on the in vitro proliferation of peripheral blood granulocyte/macrophage progenitors (CFUc) from patients with MPDs.
- To compare the response of CFUc from MPD patients to PGE1 with that of normal individuals.
- To elucidate the mechanisms underlying altered PGE1 responses in MPDs.
Main Methods:
- In vitro culture of peripheral blood and bone marrow CFUc.
- Dose-response studies with PGE1.
- Addition of colony stimulating factor (CSF) and prostaglandin antagonist SC-19220.
- Cell fractionation studies.
Main Results:
- PGE1 demonstrated dose-dependent inhibition of normal CFUc proliferation.
- CFUc from chronic myelogenous leukemia (CML) patients showed normal inhibition by PGE1, which was abrogated by CSF.
- CFUc from myelofibrosis/myeloid metaplasia (MM) patients exhibited heterogeneous responses to PGE1, with both stimulation and inhibition observed.
- PGE1 effects were blocked by SC-19220 and not mediated by adherent cell factors.
- MM patients displayed dual CFUc populations with differential PGE1 sensitivity.
Conclusions:
- Significant abnormalities exist in the in vitro response to PGE1 by CFUc from patients with MPDs.
- Deficiencies in PGE1 inhibition may contribute to the excess myelopoiesis observed in these disorders.
- These findings highlight potential therapeutic targets for managing MPDs.