Inflammasome activation promotes the progression of myelodysplastic syndrome

Inflammasomes are multiprotein complexes that sense pathogen- and damage-associated molecular patterns and induce inflammatory responses and have been implicated in the pathogenesis of myelodysplastic syndrome (MDS). However, their functional contribution to MDS progression in vivo have not yet been elucidated. Here, we investigated the effects of inflammasome inhibition in mouse models of MDS by deleting Asc, an adaptor protein that links inflammasome sensor proteins to caspase-1. Asc-deficient mice showed no significant hematopoietic defects under steady-state conditions or in competitive bone marrow reconstitution assays. In an MDS mouse model co-expressing CBL^ΔE8/9 and RUNX1^S291fs, mice developed MDS and eventually progressed to acute myeloid leukemia regardless of Asc status. However, compared with wild-type MDS mice, which progressed to lethal MDS, Asc-deficient MDS mice exhibited attenuated caspase-1 activation, delayed MDS progression, and significantly prolonged survival. Asc deficiency also substantially attenuated the MDS phenotypes induced by Tet2 deficiency. Levels of IL-1β and/or IL-18, key inflammatory cytokines produced downstream of inflammasome activation, were elevated in the bone marrow fluid of these MDS models and reduced by Asc deficiency. These findings demonstrate that ASC-dependent inflammasome signaling contributes to MDS progression in vivo and suggest that targeting inflammasome signaling may represent a potential therapeutic approach for MDS. Teaser Abstract We investigated the effects of inflammasome inhibition in mouse models of MDS by deleting Asc, an adaptor protein that links inflammasome sensor proteins to caspase-1. In an MDS mouse model, mice developed MDS and eventually progressed to acute myeloid leukemia regardless of Asc status. However, compared with wild-type MDS mice, which progressed to lethal MDS, Asc-deficient MDS mice exhibited attenuated caspase-1 activation, delayed MDS progression, and significantly prolonged survival. Asc deficiency also substantially attenuated the MDS phenotypes induced by Tet2 deficiency. These findings demonstrate that ASC-dependent inflammasome signaling contributes to MDS progression in vivo.