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dc.contributor.author | Morimoto, Yuki | en |
dc.contributor.author | Chonabayashi, Kazuhisa | en |
dc.contributor.author | Kawabata, Hiroshi | en |
dc.contributor.author | Okubo, Chikako | en |
dc.contributor.author | Yamasaki-Morita, Makiko | en |
dc.contributor.author | Nishikawa, Misato | en |
dc.contributor.author | Narita, Megumi | en |
dc.contributor.author | Inagaki, Azusa | en |
dc.contributor.author | Nakanishi, Kayoko | en |
dc.contributor.author | Nagao, Miki | en |
dc.contributor.author | Takaori-Kondo, Akifumi | en |
dc.contributor.author | Yoshida, Yoshinori | en |
dc.contributor.alternative | 森本, 有紀 | ja |
dc.contributor.alternative | 蝶名林, 和久 | ja |
dc.contributor.alternative | 川端, 浩 | ja |
dc.contributor.alternative | 大久保, 周子 | ja |
dc.contributor.alternative | 山﨑, 真紀子 | ja |
dc.contributor.alternative | 西川, 美里 | ja |
dc.contributor.alternative | 成田, 恵 | ja |
dc.contributor.alternative | 稲垣, 梓 | ja |
dc.contributor.alternative | 中西, 加代子 | ja |
dc.contributor.alternative | 長尾, 美紀 | ja |
dc.contributor.alternative | 高折, 晃史 | ja |
dc.contributor.alternative | 吉田, 善紀 | ja |
dc.date.accessioned | 2022-06-22T01:33:06Z | - |
dc.date.available | 2022-06-22T01:33:06Z | - |
dc.date.issued | 2022-02-22 | - |
dc.identifier.uri | http://hdl.handle.net/2433/274480 | - |
dc.description | 女性のX連鎖性鉄芽球性貧血患者さん由来のiPS細胞を使った病態モデルの作製と治療薬候補の発見. 京都大学プレスリリース. 2021-12-01. | ja |
dc.description.abstract | X-linked sideroblastic anemia (XLSA) is associated with mutations in the erythroid-specific δ-aminolevulinic acid synthase (ALAS2) gene. Treatment for XLSA is mainly supportive, except in pyridoxine-responsive patients. Female XLSA often represents a late onset of severe anemia, mostly due to the acquired skewing of X-chromosome inactivation. Here, we successfully generated active wild-type and mutant ALAS2 induced pluripotent stem cell (iPSC) lines from the peripheral blood cells of an affected mother and two daughters in a family with pyridoxine-resistant XLSA due to a heterozygous ALAS2 missense mutation (R227C). The erythroid differentiation potential was severely impaired in active mutant iPSC lines compared to that in active wild-type iPSC lines. Most of the active mutant iPSC-derived erythroblasts revealed an immature morphological phenotype, and some showed dysplasia and perinuclear iron deposits. Additionally, globin and HO-1 expression and heme biosynthesis in active mutant erythroblasts were severely impaired compared to that in active wild-type erythroblasts. Furthermore, genes associated with erythroblast maturation and karyopyknosis showed significantly reduced expression in active mutant erythroblasts, recapitulating the maturation defects. Notably, the erythroid differentiation ability and hemoglobin expression of active mutant iPSC-derived hematopoietic progenitor cells (HPCs) were improved by the administration of δ-aminolevulinic acid, verifying the suitability of the cells for drug testing. Administration of a DNA demethylating agent, azacitidine, reactivated the silent wild-type ALAS2 allele in active mutant HPCs and ameliorated erythroid differentiation defects, suggesting that azacitidine is a potential novel therapeutic drug for female XLSA. Our patient-specific iPSC platform provides novel biological and therapeutic insights for XLSA. | en |
dc.language.iso | eng | - |
dc.publisher | American Society of Hematology | en |
dc.rights | © 2022 by The American Society of Hematology. | en |
dc.rights | Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved. | en |
dc.rights.uri | https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode | - |
dc.subject | Red Cells, Iron, and Erythropoiesis | en |
dc.title | Azacitidine is a potential therapeutic drug for pyridoxine-refractory female X-linked sideroblastic anemia | en |
dc.type | journal article | - |
dc.type.niitype | Journal Article | - |
dc.identifier.jtitle | Blood Advances | en |
dc.identifier.volume | 6 | - |
dc.identifier.issue | 4 | - |
dc.identifier.spage | 1100 | - |
dc.identifier.epage | 1114 | - |
dc.relation.doi | 10.1182/bloodadvances.2021005664 | - |
dc.textversion | publisher | - |
dc.address | Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University; Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University | en |
dc.address | Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University; Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University | en |
dc.address | Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University; Department of Hematology, National Hospital Organization Kyoto Medical Center | en |
dc.address | Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University | en |
dc.address | Department of Clinical Laboratory, Kyoto University Hospital | en |
dc.address | Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University | en |
dc.address | Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University | en |
dc.address | Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University | en |
dc.address | Department of Clinical Laboratory, Kyoto University Hospital | en |
dc.address | Department of Clinical Laboratory, Kyoto University Hospital | en |
dc.address | Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University | en |
dc.address | Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University | en |
dc.identifier.pmid | 34781359 | - |
dc.relation.url | https://www.cira.kyoto-u.ac.jp/j/pressrelease/news/211201-120000.html | - |
dcterms.accessRights | open access | - |
datacite.awardNumber | 17J07616 | - |
datacite.awardNumber.uri | https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-17J07616/ | - |
dc.identifier.eissn | 2473-9529 | - |
jpcoar.funderName | 日本学術振興会 | ja |
jpcoar.awardTitle | 疾患iPS細胞を用いた遺伝性鉄芽球性貧血病態解明と新規治療法開発 | ja |
Appears in Collections: | Journal Articles |
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