Journal
BLOOD
Volume 133, Issue 10, Pages 1039-1048Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2018-10-844654
Keywords
-
Categories
Funding
- NCI NIH HHS [P30 CA076292] Funding Source: Medline
Ask authors/readers for more resources
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 proinflammatory signaling within the malignant clone and the bone marrow (BM) microenvironment were identified as key pathogenic drivers of myelodysplastic syndromes (MDS). In particular, S100A9-mediated NOD-like receptor protein 3 (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 expands BM myeloid-derived suppressor cells, 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/beta-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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available