A review recently published in Cancers provides a comprehensive overview of the latest developments in understanding how the bone marrow microenvironment contributes to the etiology of myelodysplastic syndrome (MDS), in particular how clonal hematopoietic stem cells (HSCs) interact with other cell types.

MDS is a heterogeneous collection of HSC disorders that predominantly arise in patients with more advanced age, with the median age of diagnosis at 70 years. The complex combinations of genetic mutations and genomic changes that drive MDS contribute to its heterogenous clinical phenotypes and disease outcomes. Although researchers have elucidated many genetic/genomic factors contributing to MDS, currently available treatments have still had limited success, prompting investigations into the bone marrow microenvironment.

Until recently, the role of the bone marrow microenvironment in the development of MDS was unclear. The authors discussed possible routes to MDS with contributions from the microenvironment. With 1 route, somatic mutations can occur in HSCs that continue to proliferate normally until increased age, genomic instability, and age-related inflammation (inflammaging) combined with external environmental cues allow them to proliferate malignantly. Alternatively, acquisition of certain mutations in HSCs, with or without additional external factors, and clonal selection can lead directly to MDS.

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In addition to this, the bone marrow contains a multitude of other cell types, including megakaryocytes, arteriolar and sinusoidal-type endothelial cells, osteolineage cells, osteoclasts, osteoblasts, non-myelinating Schwann cells, and mesenchymal stromal

cells (MSCs) as well as immune-related cells, such as myeloid derived suppressor cells (MDSCs), regulatory T cells (T-regs), dendritic cells, neutrophils, natural killer cells, monocytes, and macrophages.

Studies have reported that MDS-initiating cells (MDSICs), early HSCs with genetic abnormalities, are able to crosstalk with MSCs. MSCs and endothelial cells have been shown to be dysfunctional in MDS. Other observations have included indirect influences of T-regs on MDS-ICs via MSCs and significant increases MDSCs and monocytes in the bone marrow of patients with MDS. Furthermore, the bone marrow microenvironments of patient with MDS contains abnormal levels of cytokines, growth factors, and reactive oxygen species, all of which may directly influence the MDS-ICs.

The authors suggested that that development of therapeutic approaches that allow for an array of personalized treatment options for patients with MDS is needed, including those that target the microenvironment. For example, a number of novel agents are being tested in clinical trials, including erythropoiesis stimulating agents (eg, luspatercept), spliceosome inhibitors (eg, H3B-8800), hypoxia-inducible factor inhibitors (eg, roxadustat), monoclonal antibodies (eg, magrolimab), BCL2 inhibitors (eg, venetoclax), and p53 reactivators (eg, eprenetapopt). Other novel strategies include targeting hedgehog signaling, which is highly active in endothelial cells, and inhibiting nitric oxide to normalize vascular permeability in the bone marrow of patients with MDS.


Mian SA, Bonnet D. Nature or nurture? Role of the bone marrow microenvironment in the genesis and maintenance of myelodysplastic syndromes. Cancers (Basel). 2021;13(16):4116. doi:10.3390/cancers13164116