Abstract
Myelodysplastic syndromes (MDS) are myeloid neoplasms characterized by bone marrow dysfunction and increased risk of transformation to leukemia. MDS represent complex and diverse diseases that evolve from malignant hematopoietic stem cells and involve not only the proliferation of malignant cells but also the dysfunction of normal bone marrow. Specifically, the marrow microenvironment—both hematopoietic and stromal components—is disrupted in MDS. While microenvironmental disruption has been described in human MDS and murine models of the disease, only a few current treatments target the microenvironment, including the immune system. In this review, we will examine current evidence supporting three key interdependent pillars of microenvironmental alteration in MDS—immune dysfunction, cytokine skewing, and stromal changes. Understanding the molecular changes seen in these diseases has been, and will continue to be, foundational to developing effective novel treatments that prevent disease progression and transformation to leukemia.
Highlights
Myelodysplastic Syndrome: AMyelodysplastic syndromes (MDS) occur when mutant hematopoietic stem cells (HSCs) proliferate, giving rise to dysplastic myeloid progeny and ineffective hematopoiesis [1]
MDS may arise from precursor lesions, such as clonal hematopoiesis of indeterminate potential (CHIP), where clonal populations of HSCs carry mutations identified in hematologic malignancies [9,10]
Much is still unknown regarding MDS pathogenesis; this review aims to synthesize key research related to immune cell behavior within the MDS microenvironment, cytokine production patterns in MDS, and stromal cell contributions to disease development and progression
Summary
Myelodysplastic syndromes (MDS) occur when mutant hematopoietic stem cells (HSCs) proliferate, giving rise to dysplastic myeloid progeny and ineffective hematopoiesis [1]. The wide range of disease severity seen in MDS is due both to the variety of driver mutations and the extent to which clonal cells have overtaken normal bone marrow function. Serine and Arginine Rich Splicing Factor 2 (SRSF2) mutations influence the splicing machinery and require additional proliferative mutations [19] These findings may invoke interactions of the clone with the microenvironment, including immune cells and signals, as a mechanism of clonal expansion. The manifestations of MDS are due both to the proliferation and aberrant differentiation of mutated, malignant HSCs and their progeny, as well as the failure of normal bone marrow as clonal MDS cells take over. Much is still unknown regarding MDS pathogenesis; this review aims to synthesize key research related to immune cell behavior within the MDS microenvironment, cytokine production patterns in MDS, and stromal cell contributions to disease development and progression
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