Haematologica（2025）. https://doi.org/10.3324/haematol.2025.287951.

题目：

TGFβ-activated kinase-1 knockdown in hematopoieticstem-progenitor cells causes PANoptosis and myelodysplasticsyndrome-like disease in mice

作者：

Lei Zhang1,2,3, Wenyan Li4, Rohit Thalla2,3, Rongyao Ma1, Ryan Mack2,3, Ameet R. Kini5, AustinRunde2,3, Patrick A. Hagen2,6, Kevin Barton2,6, Jorgena Kosti-Schwartz2,5, Peter Breslin2,3,7,Hong-Long Ji8, Jiwang Zhang2,3,5*

单位：

1 Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, National

Clinical Research Center for Hematologic Diseases, MOE Engineering Center of Hematological Disease, Soochow University, Suzhou 215123, China

2 Oncology Institute, Cardinal Bernardin Cancer Canter, Loyola University Chicago Medical

Center, Maywood, IL 60153, USA

3 Department of Cancer Biology, Loyola University Chicago Medical Center, Maywood, IL

60153, USA

4 Lanzhou University Second Hospital, Key Laboratory of Urological Diseases in Gansu

Province, Lanzhou, Gansu 730030, China

5 Departments of Pathology and Radiation Oncology, Loyola University Chicago Medical Center,Maywood, IL 60153, USA

6 Department of Medicine, Loyola University Chicago Medical Center, Maywood, IL 60153,

USA

7 Departments of Biology and Molecular/Cellular Physiology, Loyola University Chicago,

Maywood, IL 60153, USA

8 Department of Surgery, Loyola University Chicago Medical Center, Maywood, IL 60153, USA

摘要：

Mutant SF3B1 (SF3B1mut) in hematopoietic stem/progenitor cells (HSPCs) 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 HSPCs 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 SF3B1mut-HSPCs. We found that TAK1 is required for the survival of HSPCs 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 HSPCs. We found that mice transplanted with Tak1KD-HSPCs developed anemia and that Ripk1 inhibition could restore blood cell counts in such anemic mice. Tak1KD-HSPCs 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 (EBs). TAK1 inhibitor could also preferentially eliminate SF3B1mut HSPCs 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 HSPCs.