Inflammasome activation promotes the progression of myelodysplastic syndrome

Inflammasomes, protein complexes that sense pathogen- and damage-associated molecular patterns and induce inflammatory responses, have been reported to be activated during the progression of myelodysplastic syndrome (MDS). However, its involvement in MDS in vivo have not yet been elucidated. Here, we investigated the effects of inflammasome inhibition in a mouse model of MDS by deleting Pycard, which encodes apoptosis-associated speck-like protein containing a CARD (ASC), a component of the inflammasome that acts as an adaptor protein linking sensor proteins to caspase-1. Pycard-deficient mice did not exhibit significant hematopoietic defects in steady-state and competitive bone marrow reconstitution settings. In an MDS mouse model co-expressing CBLdE8/9 and RUNX1S291fs (CBLdE8/9RUNX1S291fs mice), RUNX1S291fsCBLdE8/9 mice developed MDS and ultimately acute myeloid leukemia regardless of the presence or absence of ASC. However, in contrast to wild-type MDS mice, which progressed to lethal MDS, Pycard-deficient MDS mice showed attenuated caspase-1 activation in MDS cells, mitigated MDS progression, and significantly improved survival. Transcriptome analysis revealed that the activation of the inflammatory response was attenuated in Pycard-deficient MDS progenitor cells. These findings support the involvement of inflammasome activation in MDS progression and support the notion that inflammasome inhibition is a new therapeutic approach for MDS.