The microenvironment in myelodysplastic syndromes: Niche-mediated disease initiation and progression

Abstract

Myelodysplastic syndromes (MDS) are clonal disorders of hematopoietic stem and progenitor cells and represent the most common cause of acquired marrow failure. Hallmarked by ineffective hematopoiesis, dysplastic marrow, and risk of transformation to acute leukemia, MDS remains a poorly treated disease. Although identification of hematopoietic aberrations in human MDS has contributed significantly to our understanding of MDS pathogenesis, evidence now identify the bone marrow microenvironment (BMME) as another key contributor to disease initiation and progression. With improved understanding of the BMME, we are beginning to refine the role of the hematopoietic niche in MDS. Despite genetic diversity in MDS, interaction between MDS and the BMME appears to be a common disease feature, and therefore represents an appealing therapeutic target. Further understanding of the interdependent relationship between MDS and its niche is needed to delineate the mechanisms underlying hematopoietic failure and how the microenvironment can be clinically targeted. This review will provide an overview of data from human MDS and murine models supporting a role for BMME dysfunction at several steps of disease pathogenesis. While no models or human studies so far have combined all these findings, we will review current data identifying BMME involvement in each step of MDS pathogenesis, organized to reflect the chronology of BMME contribution as the normal hematopoietic system becomes myelodysplastic and MDS progresses to marrow failure and transformation. Although microenvironmental heterogeneity and dysfunction certainly add complexity to this syndrome, data are already demonstrating that targeting microenvironmental signals may represent novel therapeutic strategies for MDS treatment.

Common and different alterations of bone marrow mesenchymal stromal cells in myelodysplastic syndrome and multiple myeloma

“…Downregulation of the haematopoiesis associated genes was also observed in BM‐MSCs primed by MDS and MM cell lines, which could result in multilineage peripheral blood cytopenia in patients. Further studies will be needed to define the correlation among age and CXCL12 expression with haematopoietic function in patients 24‐26 …”

“…These genetic alterations might increase the risk of bone loss and neovascularization in MDS and MM patients which correlated with disease progression and prognosis 11,39‐41 . Hence, it is reasonable to consider anti‐angiogenic drugs as a priority for targeting BM microenvironment 24,42,43 …”

Direct modulation of the bone marrow mesenchymal stromal cell compartment by azacitidine enhances healthy hematopoiesis

“…This is in line with our previously published results showing EL08-1D2 cells to model the stem cell niche in vitro 9,13 and reiterates the dependency of MDS HSPCs on their microenvironment. [14][15][16] In vitro AZA treatment conditions for EL08-1D2 cells were established and a dose of 10 mM AZA was determined (supplemental Figure 1). EL08-1D2 cells were treated with AZA for 48 hours followed by washing.…”

Myelodysplastic syndrome patient-derived xenografts: from no options to many

“…39,40 Moreover, as the BM microenvironment has been reported to play an important role in the onset and development of MDS as well as the response to therapy, these hBMLS models are likely to be superior in mimicking key disease parameters. 43,44 Is a standardized approach possible?…”