Invited reviewBone marrow niche in the myelodysplastic syndromes
Introduction
The myelodysplastic syndromes (MDS) comprise a group of clonal hematological malignancies resulting in bone marrow (BM) failure and increased risk for progression to acute myeloid leukemia (AML) [1], [2]. Next generation DNA sequencing of hundreds of MDS patients has revealed that MDS is a highly heterogeneous multigenetic disease with sub clonal architecture [2], [3]. Recent studies of the general population found that 5–10% of older, apparently healthy individuals had acquired ≥1 myeloid gene mutation, whereas younger individuals were much less likely to have acquired clonal hematopoiesis with somatic mutations [4], [5]. Together, these results support the notion that the origin of MDS is tied to cellular senescence and provide biological rationale for why MDS most often presents in the seventh and eight decades of life [6], [7]. Clinically, MDS is often diagnosed after recognizing symptoms related to BM failure and cytopenias (e.g. fatigue, pallor, infections, bruising, bleeding). MDS has a multi-step pathogenic process. Early stages of the disease (Low to Intermediate-risk MDS) harbor rare, multipotent stem cells with somatic genomic mutations [1], [2]. This clone is associated with dysplastic hematopoiesis, excessive release of myelosuppressive cytokines, defective differentiation and genomic instability. MDS transformation to AML is a result of continuation of this process, hypermethylation, silencing of tumor suppressor genes (e.g. p15) and activation of oncogenes (e.g. Ras) [2]. Although the MDS BM is hyperproliferative, the net balance is ineffective hematopoiesis due to increased apoptosis of malignant progenitors. Apoptosis in progenitor cells is increased due to cell-intrinsic signals like BCL-2 family proteins, but BM niche signaling also promotes apoptosis via TNF-α, Fas ligand, and TGF-β [1], [3].
Whereas the majority of current MDS studies focus on genetic and epigenetic events required for normal HSC transformation into malignant hematopoietic cells, there is mounting evidence of a BM niche-based model for MDS genesis that predisposes normal HSCs to genomic mutations [4], [5].
In normal hematopoiesis, the BM niche controls hematopoietic cells via paracrine regulation, cell–cell contact and extracellular matrix (ECM) deposition. Within the BM niche, multipotent mesenchymal stromal cells (MSCs) serve an important role in regulating HSC self-renewal and differentiation [6], [7], [8]. Other important BM stromal cells include osteoblasts, osteoclasts, endothelial cells, fibroblasts, adipocytes and chondrocytes (Fig. 1) [9], [10]. Close cooperation between the BM niche and HSC balances the dynamic needs for hematopoiesis and tissue turnover [9], [11].
As for the MDS niche, the picture is ill-defined. However, emerging data provide enough concepts to allow for a framework of understanding. In a most basic frame, a cluster of atypical located immature precursors (ALIPs) physically and chemically interact with a unique orchestration of BM stromal elements (Fig. 2) [6], [7], [12].
In terms of paracrine regulation by BM stroma, the MDS niche is rife with myelotoxic cytokine imbalances compared to normal BM (Table 1) [13]. Not only do the imbalances in cytokine release depress hematopoiesis, they further perturb BM angiogenesis, ECM deposition, facilitate progressive genomic instability and contribute to the immune evasion of MDS cells [14].
Section snippets
MSCs in MDS BM niche
MSCs serve important roles in hematopoiesis and immune regulation. Several studies have indicated that impaired MSCs propagate MDS [8]. Among the MSC impairments is altered expression of Aurora kinases genes (AURK). AURKs are mitotic kinases with an important role in the regulation of G2/M phase of cell cycle, centrosomes and cytokinesis. Upregulation of AURK in cells causes dysregulation of mitosis and meiosis, which results in increased ontogenesis [14], [15]. Recent studies have indicated
The supportive role of osteoblast cells in MDS BM niche
As stromal cells in the endosteal niche, osteoblasts serve important regulatory roles in MDS BM microenvironment [24]. In addition, osteoblasts regulate the maturation and proliferation of osteoclasts through factors like receptor activator of nuclear factor kappa-B ligand (RANKL). Osteoclasts have fundamental functions in the BM niche. They are involved in HSCs support by secreting heparan sulfate, and play important roles in development and maintenance of bony skeleton of BM [28]. Osteoblasts
Vascular niche and other stromal cells in MDS bone marrow
Several types of stromal cells comprise the BM vascular niche. These are adventitial reticular CD146+ cells (ARCs) expressing Ang-1 in high levels. These cells belong to a group of osteogenic progenitors involved in development of BM heterotropic ossicles. ARCs are located near endothelial cells and are capable of direct signaling not only with HSCs but with endothelial cells, reinforcing signals to HSCs from the latter [38]. Endothelial cells play an important role in homing of hematopoietic
BM niche in low-risk and high-risk MDS
In the early stages of MDS (Low-risk MDS), increased apoptosis in hematopoietic progenitors and cytopenia is observed. In advanced stages of MDS (High risk), increased resistance to apoptosis is accompanied by further proliferation and disease transformation to AML [2], [24].
Several mechanisms of apoptosis have been studied in MDS. Apoptosis can be increased by activated T-cells because of their activity in elimination of the malignant clone, expression of Bcl-2 or reduction in hematopoietic
Next generation DNA sequencing in MDS
Next-generation sequencing (NGS) has provided new insights into the molecular etiology of MDS [56]. Early NGS studies revealed mutations of TP53, RUNX1, NRAS, and FLT3 in MDS patients, albeit at low rates. However, recent NGS studies have identified more common mutations involving epigenetic regulators such as TET2, IDH1/2, DNMT3A, ASXL1 and EZH2. In addition, multiple components of the RNA splicing machinery can be mutated in MDS, such as SF3B1, SRSF2, U2AF1, and ZRSR2. Other mutations in MDS
Conclusion and future perspective
The MDS BM microenvironment is clearly perturbed when compared to the normal BM microenvironment. The fact that MDS stromal cells often harbor different genomic mutations than their hematopoietic counterparts signals different origins. This finding also begs the question whether MDS stromal defects came first or whether the hematopoietic stem/progenitor cell defects came first. If the stromal defects came first, possibly as a consequence of cellular senescence, there are plenty of data showing
Authors’ contributions
Najmaldin Saki and Christopher R. Cogle conceived the manuscript and revised it; Elahe Khodadi and Mohammad Shahjahani wrote the manuscript; Shirin Azizidoost and June Li helped writing final version of manuscript; CRC edited the manuscript.
Conflict of interest statement
The authors declare no conflict of interest.
Acknowledgments
We wish to thank all our colleagues in Health research institute, Research Center of Thalassemia & Hemoglobinopathy. CRC was supported by a Scholar in Clinical Research Award by the Leukemia & Lymphoma Society. This work was also supported by the Gatorade Trust, which is administered by the University Of Florida Department Of Medicine.
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