Moderator of 1 Session
Presenter of 2 Presentations
MDSF Welcome and young investigator award announcements
THE NLRC4 INFLAMMASOME DRIVES MYELODYSPLASTIC SYNDROME BY LINKING EPIGENETIC REPROGRAMMING AND INNATE IMMUNE SIGNALING
Abstract
Background And Aims
Chronic inflammation increases the risk of cancer. Despite growing evidence that chronic inflammation plays a role in myelodysplastic syndromes (MDS), innate immune and inflammatory signaling pathways underlying MDS pathogenesis remain poorly defined. We aim to characterize the role that chronic inflammation plays in MDS pathogenesis and the molecular mechanisms involved.
Methods
We conducted a series of in vitro, in vivo, and in silico experiments using Tet2-deficient mice and a human MDS cell line to study the biology of hematopoietic stem and progenitor cells (HSPCs) under chronic inflammation. Bioinformatic analyses of RNA sequencing results from our mouse model and a gene expression dataset from MDS patients were performed to characterize the molecular basis.
Results
We find that mice lacking Tet2 develop a hyper-inflammatory status, which is further upregulated by LPS-induced chronic inflammation. Chimeric mice transplanted with bone marrow cells isolated from LPS-treated Tet2-deficient mice exhibit early onset of MDS phenotypes and a significantly shorter life span. Chronic inflammation further promotes the self-renewal and myeloid differentiation of Tet2-deficient HSPCs in the short term but accelerates HSC exhaustion in the long run. Transcription profiling and subsequent bioinformatic analyses reveal upregulation of the Nlrc4 inflammasome in our mouse model and human CD34+ cells from MDS patients harboring TET2 mutations. The effects of Nlrc4 deletion and Nlrc4 inhibition on MDS development are under evaluation.
Conclusions
The Nlrc4 inflammasome signaling pathway serves as a mechanistic basis for the inflammatory component of MDS pathogenesis in Tet2-deficient HSPCs. Our findings have the potential to open up new avenues for MDS therapeutics.