Thrombopoietin Stimulates Myelodysplastic Syndrome Granulocyte-Macrophage and Erythroid Progenitor Proliferation

Abstract

Thrombopoietin (TPO) has been successfully used to stimulate megakaryocyte progenitor proliferation and platelet production both in vitro and in vivo. We and other investigators have found that TPO also stimulates normal marrow colony-forming unit granulocyte-macrophage (CFU-GM) and burst-forming unit-erythroid (BFU-E) growth. In contrast to its effect on normal marrow precursors, TPO stimulates acute myelogenous leukemia (AML) progenitor proliferation in only 25% of the cases. Because the hematopoietic cells in Myelodysplastic syndrome (MDS) originate from both the normal and leukemic clones, we hypothesized that TPO may be a useful therapeutic agent for MDS. To test this hypothesis, we used fresh marrow samples taken from 14 MDS patients. We found that in the presence of fetal calf serum (FCS) and erythropoietin (EPO) TPO (5 to 40 ng/ml) MDS CFU-GM and BFU-E colony-forming cell proliferation were stimulated in a dose-dependent fashion by up to 103% and 93% respectively. This effect was similar to the stimulation obtained with optimal concentrations of granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage CSF (GM-CSF), or interleukin-3 (IL-3). Furthermore, TPO increased the colony-stimulatory effects of G-CSF, GM-CSF, IL-3, and stem cell factor (SCF) on MDS marrow cells. However, depletion of either T lymphocytes or adherent cells abrogated the effect of TPO, suggesting that the effect is not a direct one but is mediated through interaction with cytokines produced by accessory cells. Taken together, our data suggest that the therapeutic role of TPO in the management of MDS warrants further investigation.

Key Words:

• Thrombopoietin
• myelodysplastic syndrome
• hematopoiesis