Zhang Qi, Luo Yingwan, Ye Li, Wang Yuxia, Wang Lu, Yang Wenli, Lang Wei, Zhu Shuanghong, Jiang Lingxu, Jin Weimei, Mei Chen, Zhou Xinping, Ren Yanling, Ma Liya, Xu Gaixiang, Bowattage Bowatte Gedara Lakmal Vimukthi Bandara, Tong Hongyan, Sun Jie
Department of Hematology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
Zhejiang Provincial Key Laboratory of Hematopoietic Malignancy, Zhejiang University , Hangzhou, Zhejiang, China.
Exp Hematol Oncol. 2025 Jan 29;14(1):9. doi: 10.1186/s40164-025-00600-3.
Myelodysplastic Syndromes (MDS) represent a group of heterogeneous myeloid clonal diseases derived from aberrant hematopoietic stem/progenitor cells. Enhancer of zeste homolog 2 (EZH2) is an important regulator in gene expression through methyltransferase-dependent or methyltransferase-independent mechanisms. Herein, we found EZH2 inhibition led to MDS cell pyroptosis through RNA Helicase A (RHA) down-regulation induced overexpression of S100A9, a key regulator of inflammasome activation and pyroptosis. Moreover, EZH2 inhibitor reduced tumor burden and prolonged the survival of the mice transplanted with MDS cells. In summary, our results uncovered a novel pyroptosis pathway induced by EZH2 inhibition and provided a rationale for EZH2 inhibitor treatment in MDS.
骨髓增生异常综合征（MDS）是一组源自异常造血干/祖细胞的异质性髓系克隆性疾病。zeste同源物2增强子（EZH2）是通过甲基转移酶依赖性或甲基转移酶非依赖性机制调控基因表达的重要调节因子。在此，我们发现EZH2抑制通过下调RNA解旋酶A（RHA）诱导S100A9过表达，从而导致MDS细胞焦亡，S100A9是炎性小体激活和焦亡的关键调节因子。此外，EZH2抑制剂减轻了移植MDS细胞小鼠的肿瘤负担并延长了其生存期。总之，我们的研究结果揭示了一种由EZH2抑制诱导的新型焦亡途径，并为EZH2抑制剂治疗MDS提供了理论依据。
