Molecular mechanisms of platelet and stem cell rebound after 5-fluorouracil treatment

Abstract

Sublethal irradiation and 5-fluorouracil (5-FU) treatment are two commonly used myelosuppressive methods used in the study of hematopoiesis. These methods have been considered interchangeable by some researchers because the morphological changes in the bone marrow to these treatments are similar. Here, we sought to compare the responses of hematopoietic cells, stem and progenitor cells and the bone marrow microenvironment to these treatments. Although bone marrow cellularity decreased after both treatments, the underlying mechanism of the bone marrow cell regression and recovery were very different between the two models. We found: 1. Myeloid cells and lymphoid cells had different sensitivity to the different treatments. 2. Following an initial decrease in stem cell number, 5-FU treated mice had profound thrombopoietin (Tpo) dependent stem cell rebound above baseline levels. 3. Platelet rebound in 5-FU treated animals was not the result of stem cell rebound. 4. Stem cell and platelet rebound did not occur in sub-lethally irradiated mice. 5. Platelet rebound resulted from an indirect effect of 5-FU on the microenvironment cells, but not a direct effect on the stem cells. 6. Microarray studies demonstrated that up-regulation of the angiopoietin-1/Tie2 signaling pathway coincided with platelet rebound. 7. Suppression of genes involved in chromosomal organization coincided with stem cell and platelet rebound.