Feedback Signals in Myelodysplastic Syndromes: Increased Self-Renewal of the Malignant Clone Suppresses Normal Hematopoiesis

Myelodysplastic syndromes (MDS) are triggered by an aberrant hematopoietic stem cell (HSC). It is, however, unclear how this clone interferes with physiologic blood formation. In this study, we followed the hypothesis that the MDS clone impinges on feedback signals for self-renewal and differentiation and thereby suppresses normal hematopoiesis. Based on the theory that the MDS clone affects feedback signals for self-renewal and differentiation and hence suppresses normal hematopoiesis, we have developed a mathematical model to simulate different modifications in MDS-initiating cells and systemic feedback signals during disease development. These simulations revealed that the disease initiating cells must have higher self-renewal rates than normal HSCs to outcompete normal hematopoiesis. We assumed that self-renewal is the default pathway of stem and progenitor cells which is down-regulated by an increasing number of primitive cells in the bone marrow niche – including the premature MDS cells. Furthermore, the proliferative signal is up-regulated by cytopenia. Overall, our model is compatible with clinically observed MDS development, even though a single mutation scenario is unlikely for real disease progression which is usually associated with complex clonal hierarchy. For experimental validation of systemic feedback signals, we analyzed the impact of MDS patient derived serum on hematopoietic progenitor cells in vitro: in fact, MDS serum slightly increased proliferation, whereas maintenance of primitive phenotype was reduced. However, MDS serum did not significantly affect colony forming unit (CFU) frequencies indicating that regulation of self-renewal may involve local signals from the niche. Taken together, we suggest that initial mutations in MDS particularly favor aberrant high self-renewal rates. Accumulation of primitive MDS cells in the bone marrow then interferes with feedback signals for normal hematopoiesis – which then results in cytopenia.Author Summary: Myelodysplastic syndromes are diseases which are characterized by ineffective blood formation. There is accumulating evidence that they are caused by an aberrant hematopoietic stem cell. However, it is yet unclear how this malignant clone suppresses normal hematopoiesis. To this end, we generated mathematical models under the assumption that feedback signals regulate self-renewal and proliferation of normal and diseased stem cells. The simulations demonstrate that the malignant cells must have particularly higher self-renewal rates than normal stem cells – rather than higher proliferation rates. On the other hand, down-regulation of self-renewal by the increasing number of malignant cells in the bone marrow niche can explain impairment of normal blood formation. In fact, we show that serum of patients with myelodysplastic syndrome, as compared to serum of healthy donors, stimulates proliferation and moderately impacts on maintenance of hematopoietic stem and progenitor cells in vitro. Thus, aberrant high self-renewal rates of the malignant clone seem to initiate disease development; suppression of normal blood formation is then caused by a rebound effect of feedback signals which down-regulate self-renewal of normal stem and progenitor cells as well.