Nature or Nurture? Role of the Bone Marrow Microenvironment in the Genesis and Maintenance of Myelodysplastic Syndromes

Abstract

Myelodysplastic syndrome (MDS) are clonal haematopoietic stem cell (HSC) disorders driven by a complex combination(s) of changes within the genome that result in heterogeneity in both clinical phenotype and disease outcomes. MDS is among the most common of the haematological cancers and its incidence markedly increases with age. Currently available treatments have limited success, with <5% of patients undergoing allogeneic HSC transplantation, a procedure that offers the only possible cure. Critical contributions of the bone marrow microenvironment to the MDS have recently been investigated. Although the better understanding of the underlying biology, particularly genetics of haematopoietic stem cells, has led to better disease and risk classification; however, the role that the bone marrow microenvironment plays in the development of MDS remains largely unclear. This review provides a comprehensive overview of the latest developments in understanding the aetiology of MDS, particularly focussing on understanding how HSCs and the surrounding immune/non-immune bone marrow niche interacts together.

The mesenchymal compartment in myelodysplastic syndrome: Its role in the pathogenesis of the disorder and its therapeutic targeting

“…The contribution of human MDS-derived BM-MSCs for the engraftment and maintenance of MDS HSCs in mice was also corroborated in a recent study by Mian et al. ( 69 ). The authors injected patient derived HSCs into gelatin-based scaffolds that were previously seeded with autologous or allogeneic MDS-derived BM-MSCs and the construct was subsequently transplanted in mice.…”

Congenital neutropenia: disease models guiding new treatment strategies

“…Yet, many issues are still unresolved. First, it remains unknown to what extent cell extrinsic ('niche') factors contribute to disease development, as has for instance been implicated in SDS, MDS, and MPN [63,[66][67][68][69]. Second, although excessive oxidative damage, UPR and ER stress responses and ribosomal dysfunction have all been implicated in the development of neutropenia, that these represent targetable vulnerabilities is still modest.…”

Increasing Complexity of Molecular Landscapes in Human Hematopoietic Stem and Progenitor Cells during Development and Aging

“…Although not the focus of this manuscript, alterations in the aged bone marrow microenvironment (e.g., in stromal and immune cells, cytokine/chemokine/extracellular matrix production and inflamm-aging) may lead to changes (e.g., of location, regulation, function) in HSPCs and support their evolution to hematological malignancies. The studies, which support these conclusions [ 19 , 250 , 273 , 274 , 275 , 276 , 277 ], are not reiterated here, except to highlight the controversy that surrounds the clonal origin of MDS MSC and MDS associated gene mutations or chromosomal rearrangements in MSCs that contribute to MDS progression, and which are described in detail in recent reviews [ 250 , 278 , 279 ]. Initial experiments in mice demonstrated that disruption of hematopoiesis associated with progression to an MDS-like disorder (characterized by anemia, thrombocytopenia, reduced B lymphoid cells and increased myeloid cells) occurred when the Dicer1 gene was deleted in murine osteoprogenitor cells [ 280 ].…”