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.
Helmholtz Institute for Biomedical Engineering, RWTH Aachen University Medical School, Aachen, Germany.
Thomas
T
Walenda
Interdisciplinary Center of Scientific Computing (IWR), Institute of Applied Mathematics, University of Heidelberg, Heidelberg, Germany.
Thomas
T
Stiehl
Helmholtz Institute for Biomedical Engineering, RWTH Aachen University Medical School, Aachen, Germany.
Hanna
H
Braun
Department of Hematology, Oncology and Clinical Immunology, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
Julia
J
Fröbel
Department of Medicine V, Medical Center, University of Heidelberg, Heidelberg, Germany.
Anthony D
AD
Ho
Department of Hematology, Oncology and Clinical Immunology, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
Thomas
T
Schroeder
Department of Obstetrics and Gynecology, RWTH Aachen University Medical School, Aachen, Germany.
Tamme W
TW
Goecke
Department for Orthopedics, RWTH Aachen University Medical School, Aachen, Germany.
Björn
B
Rath
Department of Hematology, Oncology and Clinical Immunology, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
Ulrich
U
Germing
Interdisciplinary Center of Scientific Computing (IWR), Institute of Applied Mathematics, University of Heidelberg, Heidelberg, Germany.
Anna
A
Marciniak-Czochra
Helmholtz Institute for Biomedical Engineering, RWTH Aachen University Medical School, Aachen, Germany.
Wolfgang
W
Wagner
D016022:Case-Control Studies; D004797:Enzyme-Linked Immunosorbent Assay; D005246:Feedback; D006410:Hematopoiesis; D006801:Humans; D009190:Myelodysplastic Syndromes / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology