PANoptosis in the pathogenesis of myelodysplastic syndromes

Myelodysplastic syndromes (MDS) are a heterogeneous group of pre-leukemic diseases marked by ineffective bone marrow (BM) hematopoiesis, peripheral cytopenia, morphologic dysplasia, and an increased risk of leukemic transformation. Increased programmed cell death (PCD) of hematopoietic stem/progenitor cells (HSPCs) and its associated inflammatory BM microenvironment have been speculated to be one of the major causes of ineffective hematopoiesis. PANoptosis is a collective term for three types of PCD: pyroptosis, apoptosis, and necroptosis. All three are mediated by a very large protein complex called a PANoptosome, composed of the key mediators of the three types of PCD. We reported that the diseased cells in MDS with genetic abnormalities, especially spliceosome mutations, show aberrant hypersensitivity to PANoptotic stimuli. Our study suggests that increased PANoptosis of BM HSPCs is one of the reasons for the ineffective hematopoiesis in MDS patients, and targeting PANoptosis may be a novel treatment strategy for MDS. Here we summarize recent advances in research into PANoptosis and discuss the potential role of PANoptosis in the pathogenesis of MDS. We discuss the potential mechanisms for targeting PANoptotic pathways to treat MDS.