Y. Kamimura-Aoyagi , Y. Harada , K. Nomura , N. Matsunuma , K. Yuki , H. Kobayashi , Y. Hayashi , A. Hijikata , H. Harada
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Although the correlation between chronic inflammation and ineffective hematopoiesis is demonstrated in forming MDS pathogenesis, the detailed mechanisms remain unclear.</p></div><div><h3>Methods</h3><p>Recently, we established a new MDS with low blasts (MDS-LB) model (<em>CBL<sup>ΔE8/9</sup>-RUNX1<sup>S291fs</sup></em> mice) , which recapitulates MDS-LB pathogenesis such as pancytopenia and chronic inflammation, by introducing these two mutations into murine hematopoietic stem and progenitor cells (HSC/Ps) .</p></div><div><h3>Results</h3><p>MDS model mice exhibited excessive mitochondrial fragmentation due to Drp1 activation in HSC/Ps. Importantly, pharmacological inhibition of mitochondrial fragmentation rescued leukocytopenia and dysplasia formation in MDS mice by suppressing inflammatory signaling activation, suggesting that mitochondrial fragmentation could be a new therapeutic target of MDS. Given that mitochondrial fragmentation is related to MDS pathogenesis, we hypothesized that mitochondrial fragmentation can be used for morphological diagnosis of MDS. Differential diagnosis of patients with non-MDS cytopenia and MDS-LB has been challenging. We assessed mitochondrial morphology in bone marrow samples from 10 healthy individuals and 141 patients before disease-modifying therapy. The percentage of cells with mitochondrial fragmentation was significantly increased in patients with MDS-LB, compared with that in patients with cytopenia without dysplasia and gene abnormality (mean 50.7% vs 22.4%, P<0.001, cutoff value 30.8%). The calculated cutoff value clearly distinguishes patients with MDS-LB and non-MDS cytopenia.</p></div><div><h3>Conclusions</h3><p>These data suggest that mitochondrial fragmentation can be not only a new therapeutic target of MDS-LB but also one category of dysplasia that can diagnose MDS-LB.</p></div>","PeriodicalId":38435,"journal":{"name":"Leukemia Research Reports","volume":null,"pages":null},"PeriodicalIF":0.7000,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2213048924000141/pdfft?md5=eaf437a90e97a820f57941330d565a3f&pid=1-s2.0-S2213048924000141-main.pdf","citationCount":"0","resultStr":"{\"title\":\"MITOCHONDRIAL FRAGMENTATION IS A NEW THERAPEUTIC TARGET AND DIAGNOSTIC CRITERIA FOR MYELODYSPLASTIC SYNDROMES.\",\"authors\":\"Y. Kamimura-Aoyagi , Y. Harada , K. Nomura , N. Matsunuma , K. Yuki , H. Kobayashi , Y. Hayashi , A. Hijikata , H. Harada\",\"doi\":\"10.1016/j.lrr.2024.100424\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Introduction</h3><p>Myelodysplastic syndromes (MDS) are characterized by persistent of cytopenia, gene abnormalities, and dysplasia. Although the correlation between chronic inflammation and ineffective hematopoiesis is demonstrated in forming MDS pathogenesis, the detailed mechanisms remain unclear.</p></div><div><h3>Methods</h3><p>Recently, we established a new MDS with low blasts (MDS-LB) model (<em>CBL<sup>ΔE8/9</sup>-RUNX1<sup>S291fs</sup></em> mice) , which recapitulates MDS-LB pathogenesis such as pancytopenia and chronic inflammation, by introducing these two mutations into murine hematopoietic stem and progenitor cells (HSC/Ps) .</p></div><div><h3>Results</h3><p>MDS model mice exhibited excessive mitochondrial fragmentation due to Drp1 activation in HSC/Ps. Importantly, pharmacological inhibition of mitochondrial fragmentation rescued leukocytopenia and dysplasia formation in MDS mice by suppressing inflammatory signaling activation, suggesting that mitochondrial fragmentation could be a new therapeutic target of MDS. Given that mitochondrial fragmentation is related to MDS pathogenesis, we hypothesized that mitochondrial fragmentation can be used for morphological diagnosis of MDS. Differential diagnosis of patients with non-MDS cytopenia and MDS-LB has been challenging. We assessed mitochondrial morphology in bone marrow samples from 10 healthy individuals and 141 patients before disease-modifying therapy. The percentage of cells with mitochondrial fragmentation was significantly increased in patients with MDS-LB, compared with that in patients with cytopenia without dysplasia and gene abnormality (mean 50.7% vs 22.4%, P<0.001, cutoff value 30.8%). The calculated cutoff value clearly distinguishes patients with MDS-LB and non-MDS cytopenia.</p></div><div><h3>Conclusions</h3><p>These data suggest that mitochondrial fragmentation can be not only a new therapeutic target of MDS-LB but also one category of dysplasia that can diagnose MDS-LB.</p></div>\",\"PeriodicalId\":38435,\"journal\":{\"name\":\"Leukemia Research Reports\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":0.7000,\"publicationDate\":\"2024-01-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.sciencedirect.com/science/article/pii/S2213048924000141/pdfft?md5=eaf437a90e97a820f57941330d565a3f&pid=1-s2.0-S2213048924000141-main.pdf\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Leukemia Research Reports\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S2213048924000141\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q4\",\"JCRName\":\"HEMATOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Leukemia Research Reports","FirstCategoryId":"1085","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2213048924000141","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q4","JCRName":"HEMATOLOGY","Score":null,"Total":0}
MITOCHONDRIAL FRAGMENTATION IS A NEW THERAPEUTIC TARGET AND DIAGNOSTIC CRITERIA FOR MYELODYSPLASTIC SYNDROMES.
Introduction
Myelodysplastic syndromes (MDS) are characterized by persistent of cytopenia, gene abnormalities, and dysplasia. Although the correlation between chronic inflammation and ineffective hematopoiesis is demonstrated in forming MDS pathogenesis, the detailed mechanisms remain unclear.
Methods
Recently, we established a new MDS with low blasts (MDS-LB) model (CBLΔE8/9-RUNX1S291fs mice) , which recapitulates MDS-LB pathogenesis such as pancytopenia and chronic inflammation, by introducing these two mutations into murine hematopoietic stem and progenitor cells (HSC/Ps) .
Results
MDS model mice exhibited excessive mitochondrial fragmentation due to Drp1 activation in HSC/Ps. Importantly, pharmacological inhibition of mitochondrial fragmentation rescued leukocytopenia and dysplasia formation in MDS mice by suppressing inflammatory signaling activation, suggesting that mitochondrial fragmentation could be a new therapeutic target of MDS. Given that mitochondrial fragmentation is related to MDS pathogenesis, we hypothesized that mitochondrial fragmentation can be used for morphological diagnosis of MDS. Differential diagnosis of patients with non-MDS cytopenia and MDS-LB has been challenging. We assessed mitochondrial morphology in bone marrow samples from 10 healthy individuals and 141 patients before disease-modifying therapy. The percentage of cells with mitochondrial fragmentation was significantly increased in patients with MDS-LB, compared with that in patients with cytopenia without dysplasia and gene abnormality (mean 50.7% vs 22.4%, P<0.001, cutoff value 30.8%). The calculated cutoff value clearly distinguishes patients with MDS-LB and non-MDS cytopenia.
Conclusions
These data suggest that mitochondrial fragmentation can be not only a new therapeutic target of MDS-LB but also one category of dysplasia that can diagnose MDS-LB.