Pathogenesis of myelodysplastic syndromes by excessive mitochondrial fragmentation
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- HAYASHI Yoshihiro
- Laboratory of Oncology, Tokyo University of Pharmacy and Life Sciences Laboratory of Cancer Pathobiology and Therapeutics, Ritsumeikan University
Bibliographic Information
- Other Title
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- ミトコンドリア断片化による骨髄異形成症候群の発症機構
Description
<p>Myelodysplastic syndromes (MDS) are a group of heterogenous hematopoietic stem cell (HSC) malignancies characterized by ineffective hematopoiesis in which clonal progenitor expansion occurs alongside impaired myelopoiesis. Inflammatory signaling activation due to dysregulated innate immunity is also a hallmark of MDS pathogenesis. We recently established a useful preclinical tool that recapitulates bona fide MDS phenotypes and gene expression profiles based on previously unreported co-mutations discovered during our clinical surveillance of mutations in patients with MDS. Notably, we focused unbiased transcriptome analysis on determining the distinct underlying mediators of MDS etiology, and identified excessive mitochondrial fission-mediated fragmentation in mutant HSCs and progenitors (HSC/Ps). We confirmed excessive mitochondrial fragmentation in HSC/Ps obtained from patients with MDS regardless of the mutational profile. Importantly, in vivo pharmacological inhibition of mitochondrial fission significantly attenuated inflammatory signaling activation, dysplasia formation and ineffective hematopoiesis phenotype, and prolonged survival of MDS mice, suggesting that excessive mitochondrial fragmentation could be a fundamental trigger of MDS pathogenesis. These findings provide new insights into the mechanistic basis of ineffective hematopoiesis, and a clue for targeting bone marrow failure caused by ineffective hematopoiesis in MDS.</p>
Journal
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- Rinsho Ketsueki
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Rinsho Ketsueki 65 (4), 249-254, 2024
The Japanese Society of Hematology
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Keywords
Details 詳細情報について
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- CRID
- 1390018506585381888
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- ISSN
- 18820824
- 04851439
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- Text Lang
- ja
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- Data Source
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- JaLC
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- Abstract License Flag
- Disallowed