Analysis of the mechanisms underlying clonal hematopoiesis in patients with acquired aplastic anemia
| Project/Area Number |
16H05335
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Hematology
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| Research Institution | Kanazawa University |
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Principal Investigator |
Nakao Shinji 金沢大学, 医学系, 教授 (70217660)
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| Co-Investigator(Renkei-kenkyūsha) |
Yoshida Yoshinori 京都大学, iPS細胞研究所, 准教授 (20447965)
Kishi Hiroyuki 富山大学, 大学院医学薬学研究部, 教授 (60186210)
Hosomichi Kazuyoshi 金沢大学, 医学系, 准教授 (50420948)
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000)
Fiscal Year 2018: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2017: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2016: ¥8,320,000 (Direct Cost: ¥6,400,000、Indirect Cost: ¥1,920,000)
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| Keywords | 再生不良性貧血 / クローン性造血 / HLA / 細胞傷害性T細胞 / 自己抗原 / HLAクラスIアレル欠失 / HLAクラスIアレル欠失血球 / CD109 / HLAクラスI欠失 / 6pLOH / ゲノム変異 / iPS細胞 / T細胞レセプター / 体細胞変異 / HLA欠失 |
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| Outline of Final Research Achievements |
Acquired aplastic anemia (AA) is a kind of autoimmune disease that is induced by the cytotoxic T lymphocyte attack against hematopoietic stem progenitor cells (HSPCs) although its exact pathogenesis remains unclear. In some patients with AA, a limited number of HSPCs clonally proliferate and support hematopoiesis without showing a tendency toward the development of hematologic malignancies. We investigated the mechanisms underlying such clonal hematopoiesis in AA patients, and found that abnormal leukocytes that lack HLA class I alleles due to loss-of-function mutations in limited HLA class I genes such as B*40:02、A*02:06 and B*54:01 are often detectable. Of particular interest, 33% of the patients shared a common nonsense mutation across different HLA alleles, that also causes the loss of corresponding HLA alleles and is therefore thought to serves as a reliable marker of immune pathophysiology of AA.
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| Academic Significance and Societal Importance of the Research Achievements |
再不貧では、第6染色体短腕のloss of heterozygosity (6pLOH)によってHLAクラスIアレルを欠失した白血球が検出されることが我々の研究によって分かっていたが、欠失するハプロタイプ中のどのHLAが自己抗原を提示しているかは不明であった。本研究により、再不貧はHLA-B*40:02、B*54:01などの限られたHLAアレルが造血幹細胞抗原をTリンパ球に提示することによって起こる自己免疫疾患であることが明らかになった。これらの特定のアレルを持つ例のTリンパ球を調べれば、自己抗原が明らかになる可能性が高い。また、HLAの共通変異の検出は免疫病態の証明に非常に有用である。
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Report
(4 results)
Research Products
(11 results)
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[Journal Article] Identification of an HLA class I allele closely involved in the auto-antigen presentation in acquired aplastic anemia2017
Author(s)
Zaimoku Y, Takamatsu H, Hosomichi K, Ozawa T, Nakagawa N, Imi T, Maruyama H, Katagiri T, Kishi H, Tajima A, Muraguchi A, Kashiwase K, Nakao S
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Journal Title
Blood
Volume: 印刷中
Issue: 21
Pages: 2908-2916
DOI
Related Report
Peer Reviewed / Open Access
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[Presentation] Loss-of-Function Mutations in HLA-Class I Alleles in Acquire Aplastic Anemia: Evidence for the Involvement of Limited Class I Alleles in the Auto-Antigen Presentation of Aplastic Anemia2018
Author(s)
Mizumaki H, Hosomich K, Tanabe M, Yoroidaka T, Imi T, Zaimoku Y, Hosokawa K, Katagiri T, Takamatsu H, Ozawa T, Azuma F, Kishi H, Tajima A, Nakao S
Organizer
The 60st American Society of Hematology Annual Meeting and Exposition
Related Report
Int'l Joint Research
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[Presentation] Identification of T Cell Receptors Specific to Antigens Presented By HLA-B5401 onIPS Cell-Derived Hematopoietic Stem Cells in a Patient with Acquired Aplastic Anemia Carrying B5401-Lacking Leukocytes2017
Author(s)
Noriharu Nakagawa, Mahmoud I Elbadry, Yoshiki Akatsuka, Hiroshi Hamana, Kiyomi Shitaoka, Yoshinori Yoshida, Kazuhisa Chonabayashi, Tatsuya Imi, Yoshitaka Zaimoku, Katsuto Takenaka, Hiroshi Fujiwara, Hiroyuki Kishi, Shinji Nakao
Organizer
59th American Society of Hematology
Related Report
Int'l Joint Research
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