The central role of inflammatory signaling in the pathogenesis of myelodysplastic syndromes

David A. Sallman and Alan List


In cancer biology, tumor promoting inflammation and an inflammatory microenvironment play a vital role in disease pathogenesis. In the past decade, aberrant innate immune activation and pro-inflammatory signaling within the malignant clone and the bone marrow microenvironment were identified as key pathogenic drivers of myelodysplastic syndromes (MDS). In particular, S100A9-mediated NLRP3 inflammasome activation directs an inflammatory, lytic form of cell death termed pyroptosis that underlies many of the hallmark features of the disease. This circuit and accompanying release of other danger-associated molecular patterns (DAMPs) expands bone marrow myeloid derived suppressor cells (MDSC), creating a feed-forward process propagating inflammasome activation. Furthermore, somatic gene mutations of varied functional classes license the NLRP3 inflammasome to generate a common phenotype with excess reactive oxygen species generation, Wnt/β-catenin-induced proliferation, cation flux-induced cell swelling and caspase-1 activation. Recent investigations have shown that activation of the NLRP3 inflammasome complex has more broad reaching importance, particularly as a possible disease-specific biomarker for MDS, and mechanistically, as a driver of cardiovascular morbidity/mortality in individuals with age-related, clonal hematopoiesis. Recognition of the mechanistic role of aberrant innate immune activation in MDS provides a new perspective for therapeutic development that could usher in a novel class of disease modifying agents.

  • Submitted October 9, 2018.
  • Accepted December 6, 2018.