The NLRC4 Inflammasome Drives Myelodysplastic Syndrome by Linking Epigenetic Reprogramming and Innate Immune...

Myelodysplastic syndromes (MDS), which are hematopoietic stem cell malignancies, are often accompanied by signs of chronic inflammation, that can in turn drive the pathogenetic process. The precise mechanisms dysregulating inflammatory and innate immune signaling in MDS hematopoietic stem and progenitor cells (HSPCs) remain under investigation. We report that mice lacking Tet2 developed a hyper-inflammatory state, which can be further fueled by LPS-induced inflammation. This chronic inflammation temporarily promotes the self-renewal and myeloid differentiation of Tet2-deficient HSPCs; however, it ultimately accelerates HSC exhaustion and triggers MDS development in chimeric mouse models. Driving this phenotype was the activation of the NLRC4 inflammasome pathway. Notably, Nlrc4 depletion in Tet2-deficient mice impaired MDS development and improved the survival of these mice. These findings uncover a novel mechanistic basis for the MDS-associated inflammation and provide new targeting opportunities in its management.