Friday, April 4, 2025
4/4/2025
Targeting PANoptotic pathways for Myelodysplastic Syndromes treatment - Targeting PANoptotic pathways for MDS treatment Abstract Myelodysplastic syndromes (MDS) are a heterogeneous group of bone marrow (BM) failure diseases which develop from mutant clonal hematopoietic stem/progenitor cells (HSPCs). All MDS patients suffer from peripheral blood cytopenia-related symptoms, and many of them die of cytopenia-associated complications. 30-40% of MDS cases transform into acute myeloid leukemia (AML) and die within 4–6 months of AML transformation. Current treatment for MDS is focused on stimulating blood cell production to reduce symptoms and morbidity, as well as preventing AML transformation. Hypomethylating agents (HMA) are the first choice of therapy, which induces clinical responses in >50% of patients. However, due to the failure to eliminate MDS-HSPCs, almost all patients become refractory. Splice inhibitor treatment is in early clinical trials for patients with spliceosome mutations and shows promising results. The clinical outcomes of MDS patients are still very poor. Cytopenia in MDS is a result of ineffective hematopoiesis, which is associated with impaired differentiation and increased programmed cell death (PCD) of mutant HSPCs and an inflammatory BM environment, which inhibits blood cell production from remaining healthy HSPCs, whereas AML transformation is a result of the clonal evolution of mutant HSPCs. We found increased PANoptosis in BM samples of most MDS patients, especially in patients with mutations of splice factors SF3B1 and SRSF2. PANoptosis is a collective term referring to pyroptosis, apoptosis and necroptosis. RIPK1 is a master regulator of PANoptosis which kinase activity is required for all 3 types of PCD. In normal hematopoietic cells (HCs), PANoptosis is restricted by TAK1- and TBK1-mediated inhibitory phosphorylation and Caspase 8 (CASP8)-mediated cleavage of RIPK1. SF3B1 and SRSF2 are commonly mutated in MDS causing mis-splicing of TAK1 and CASP8, respectively, resulting in hypersensitivity of HCs to PANoptosis. We found that hematopoietic-specific Tak1 knockdown or Casp8 knockout in mice causes MDS-like disease with a phenotype similar to SF3B1+/K700E and SRSF2+/P95H knock-in mice. We also found that either HMA or splice inhibitor treatment induces PANoptosis in SF3B1+/K700E and SRSF2+/P95H HCs. However mutant Lin-c-Kit+Sca1+ HSPCs are relatively resistant to PANoptosis due to the activation of TBK1. We hypothesize that inhibition of RIPK1 will restore blood cell counts, while inhibition of TBK1 will help to prevent AML transformation by facilitating the elimination of mutant HSPCs in SF3B1 and SRSF2-mutant MDS. We want to test such an idea using SF3B1+/K700E and SRSF2+/P95H mice. We will first determine whether genetic inactivation of Ripk1 can prevent MDS and also whether pharmacologic inhibition of Ripk1 can restore blood cell counts after MDS develops. We will then determine whether deletion of Tbk1 can prevent MDS and whether pharmacologic inhibition of Tbk1 can eliminate the mutant HSPCs in combination with an HMA or a splice inhibitor. Finally, we will test the effect of RIPK1 and TBK1 inhibition on MDS patient samples. Our study will provide solid conclusions that will translate these new treatment strategies into a clinical trial.
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