TGFβ-activated kinase-1 knockdown in hematopoietic stem-progenitor cells causes PANoptosis and myelodysplastic syndrome-like disease in mice.

Mutant SF3B1 (SF3B1mut) in hematopoietic stem/progenitor cells (HSPC) primarily affects erythropoiesis, resulting in myelodysplastic syndromes (MDS) with refractory macrocytic anemia and ring sideroblasts. SF3B1mut results in aberrant splicing of a large number of transcripts in HSPC due to the alternative use of cryptic splice sites. Aberrant splicing of Tmem14c and Abcb7 has been shown to be the cause of the ring sideroblasts. However, the key mis-spliced gene(s) that drive macrocytic anemia have not been well-determined. Mis-splicing and downregulation of TAK1 pre-mRNA was detected in SF3B- 1mut-HSPC. We found that TAK1 is required for the survival of HSPC by restricting RIPK1-dependent and -independent PANoptosis. PANoptosis was increased in bone marrow samples from SF3B1mut-MDS patients. To study whether TAK1-downregulation is the cause of anemia in SF3B1mut-MDS, we knocked down Tak1 (Tak1KD) in mouse HSPC. We found that mice transplanted with Tak1KD-HSPC developed anemia and that Ripk1 inhibition could restore blood cell counts in such anemic mice. Tak1KD-HSPC are highly sensitive to TAK1 inhibitor- or cIAP inhibitor-induced PANoptosis. Furthermore, RIPK1 inhibition could also correct differentiation and survival defects of SF3B1mut human erythroblasts. TAK1 inhibitor could also preferentially eliminate SF3B1mut HSPC from MDS patient samples. Our study suggests that SF3B1mut MDS can be treated by either inhibition of RIPK1-PANoptotic signaling to restore blood cell counts or activation of PANoptosis to eliminate the mutant HSPC.