Mitochondrial Fragmentation Triggers Ineffective Hematopoiesis in Myelodysplastic Syndromes
Mitochondrial Fragmentation Triggers Ineffective Hematopoiesis in Myelodysplastic Syndromes
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DOI：
10.1158/2159-8290.cd-21-0032
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发表时间：
2022-01-01
期刊：
影响因子：
28.2
通讯作者：
Harada, Hironori
中科院分区：
文献类型：
--
作者：
Aoyagi, Yasushige;Hayashi, Yoshihiro;Harada, Hironori
无效的造血是导致骨髓增生异常综合征(MDS)发病的一个基本过程。然而，MDS无效造血的病理生物学介质仍不清楚。在这里，我们证明了在突变的造血干细胞和祖细胞(HSC/P)中过度的线粒体碎裂会在MDS中触发无效的造血。用RUNX1突变体对CBL外显子缺失的小鼠建模，不仅概括了临床上相关的MDS表型，而且还概括了明显的MDS相关基因特征。机制上，HSC/Ps依赖动力蛋白相关蛋白1(Dynamin-Related Protein 1，DRp1)的线粒体过度碎裂导致产生过多的活性氧，诱导炎症信号的激活，促进随后的异型增生的形成和粒细胞的功能障碍。线粒体断裂在MDS患者中普遍存在。药物抑制Drp1可减轻MDS小鼠的线粒体碎裂和挽救无效的造血表型。这些发现提供了对无效造血的机械性见解，并表明线粒体动力学失调可能是MDS骨髓衰竭的治疗靶点。意义：我们证明线粒体过度碎裂是一种基本的病理生物学现象，可在MDS中引发异型增生形成和无效的造血。我们的发现提供了对无效造血的机械性见解，并建议将失调的线粒体动力学作为治疗MDS的靶点。
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/P) triggers ineffective hematopoiesis in MDS. Mouse modeling of CBL exon deletion with RUNX1 mutants, previously unreported comutations in patients with MDS, 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 reactive oxygen species production, induced infl ammatory signaling activation, and promoted subsequent dysplasia formation and impairment of granulopoiesis. Mitochondrial fragmentation was generally observed in patients with MDS. Pharmacologic inhibition of DRP1 attenuated mitochondrial fragmentation and rescued ineffective hematopoiesis phenotypes in mice with MDS. These fi ndings provide mechanistic insights into ineffective hematopoiesis and indicate that dysregulated mitochondrial dynamics could be a therapeutic target for bone marrow failure in MDS. SIGNIFICANCE: We demonstrated that excessive mitochondrial fragmentation is a fundamental pathobiological phenomenon that could trigger dysplasia formation and ineffective hematopoiesis in MDS. Our findings provide mechanistic insights into ineffective hematopoiesis and suggest dysregulated mitochondrial dynamics as a therapeutic target for treating MDS.