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The Marrow Microenvironment in Myelodysplastic Syndromes

المؤلف:  Hoffman, R., Benz, E. J., Silberstein, L. E., Heslop, H., Weitz, J., & Salama, M. E.

المصدر:  Hematology : Basic Principles and Practice

الجزء والصفحة:  8th E , P985

2026-10-18

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 MDS develops not in isolation but within the microenvironment of the bone marrow stroma, also called the “hematopoietic niche”. Under normal circumstances, hematopoiesis is in part regulated by paracrine signals released from non-hematopoietic mesenchymal cells,209 and some of these processes are dysregulated in MDS. For example, some patients with MDS have abnormal circulating levels of cytokines known to affect hematopoiesis, including monocyte colony-stimulating factor (M-CSF), interleukin 1a, and granulocyte–monocyte colony-stimulating factor (GM-CSF), and hematopoietic cells from MDS patients respond abnormally to these cytokines compared to cells from healthy controls. Additionally, hematopoietic progenitor cells transplanted into older mice display a narrower range of clonal expansion than identical cells transplanted into younger mice, suggesting that an aging niche might exert selective pressure on dominant HPC clones. Conditional deletion of the gene encoding dicer1, a microRNA processing enzyme, in osteo progenitor cells can induce myelodysplasia and secondary AML in mice, and mesenchymal cells of MDS patients display altered expression of DICER and DROSHA, another microRNA-processing enzyme. Finally, introduction of an activating B-catenin mutation in mouse osteoblasts can induce the development of AML through induction of the Notch ligand jagged1, which leads to Notch activation in HSCs.

While these studies show that non-cell autonomous features of the marrow microenvironment can induce myelodysplasia in model systems, it is not clear whether this is a dominant mechanism of MDS initiation in humans. The majority of MDS cases have at least one detectable genetic or karyotypic abnormality, suggesting that cell-intrinsic dysregulation is usually necessary for disease propagation. Moreover, many of the mutations common in MDS, including those in TET2, DNMT3A, and many of the splicing factor genes, lead to altered inflammatory signaling in terminally differentiated leukocytes. It is therefore likely that at least some microenvironmental dysfunction is a consequence of MDS clones, not a cause.