线粒体
细胞凋亡
细胞生物学
骨髓
髓样
程序性细胞死亡
作者
Yasushige Aoyagi,Yoshihiro Hayashi,Yuka Harada,Kwangmin Choi,Natsumi Matsunuma,Daichi Sadato,Yuki Maemoto,Akihiro Ito,Shigeru Yanagi,Daniel T. Starczynowski,Hironori Harada
出处
期刊:Cancer Discovery
[American Association for Cancer Research]
日期:2021-08-30
标识
DOI:10.1158/2159-8290.cd-21-0032
摘要
Ineffective hematopoiesis is a fundamental process leading to the pathogenesis of myelodysplastic syndromes (MDS). However, the pathobiological mediators of ineffective hematopoiesis in MDS remain unclear. Here, we demonstrated that overwhelming mitochondrial fragmentation in mutant hematopoietic stem cells and progenitors (HSC/Ps) triggers ineffective hematopoiesis in MDS. Mouse modeling of CBL exon-deletion with RUNX1 mutants, previously unreported co-mutations in MDS patients, recapitulated not only clinically relevant MDS phenotypes but also a distinct MDS-related gene signature. Mechanistically, dynamin-related protein 1 (DRP1)-dependent excessive mitochondrial fragmentation in HSC/Ps led to excessive ROS production, induced inflammatory signaling activation, and promoted subsequent dysplasia formation and impairment of granulopoiesis. Mitochondrial fragmentation was generally observed in patients with MDS. Pharmacological inhibition of DRP1 attenuated mitochondrial fragmentation and rescued ineffective hematopoiesis phenotypes in MDS mice. These findings provide mechanistic insights into ineffective hematopoiesis and indicate that dysregulated mitochondrial dynamics could be a therapeutic target for bone marrow failure in MDS.
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