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Suppression of GPR56 expression by pyrrole-imidazole polyamide represents a novel therapeutic drug for AML with high EVI1 expressio
http://hdl.handle.net/10458/6665
http://hdl.handle.net/10458/6665a05da6e6-400a-4b30-be29-6aacef1baab0
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youshi.pdf (1.1 MB)
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shinsakekka.pdf (452.2 kB)
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honbun.pdf (1.4 MB)
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| Item type | 学位論文 / Thesis or Dissertation(1) | |||||
|---|---|---|---|---|---|---|
| 公開日 | 2020-06-21 | |||||
| タイトル | ||||||
| タイトル | Suppression of GPR56 expression by pyrrole-imidazole polyamide represents a novel therapeutic drug for AML with high EVI1 expressio | |||||
| タイトル | ||||||
| タイトル | GPR56の転写を阻害するピロール-イミダゾールポリアミドはEVIl高発現AMLの新規治療薬となる | |||||
| 言語 | en | |||||
| 言語 | ||||||
| 言語 | eng | |||||
| 資源タイプ | ||||||
| 資源タイプ識別子 | http://purl.org/coar/resource_type/c_db06 | |||||
| 資源タイプ | doctoral thesis | |||||
| アクセス権 | ||||||
| アクセス権 | open access | |||||
| アクセス権URI | http://purl.org/coar/access_right/c_abf2 | |||||
| 著者 |
Hasi, Rani Saha
× Hasi, Rani Saha |
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| 公開者 | ||||||
| 出版者 | Elsevier | |||||
| 抄録 | ||||||
| 内容記述タイプ | Abstract | |||||
| 内容記述 | G protein-coupled receptor 56 (GPR56) is highly expressed in acute myeloid leukemia (AML) cells with high EVI1 expression (EVI1high AML). Because GPR56 is a transcriptional target of EVI1 and silencing of GPR56 expression induces apoptosis, we developed a novel drug to suppress GPR56 expression in EVI1high AML cells. For this purpose, we generated pyrrole-imidazole (PI) polyamides specific to GPR56 (PIP/56-1 or PIP/56-2) as nuclease-resistant novel compounds that interfere with the binding of EVI1 to the GPR56 promoter in a sequence-specific manner. Treatment of EVI1high AML cell lines (UCSD/AML1 and Kasumi-3) with PIP/56-1 or PIP/56-2 effectivelysuppressed GPR56 expression by inhibiting binding of EVI1 to its promoter, leading to suppression of cell growth with increased rates of apoptosis. Moreover, intravenous administration of PIP/56-1 into immunodeficient Balb/c-RJ mice subcutaneously transplanted with UCSD/AML1 cells significantly inhibited tumor growth and extended survival. Furthermore, organ infiltration by leukemia cells in immunodeficient Balb/c-RJ mice, which were intravenously transplanted using UCSD/AML1 cells, was successfully inhibited by PIP/56-1 treatment with no apparent effects on murine hematopoietic cells. In addition, PIP treatment did not inhibit colony formation of human CD34+ progenitor cells. 1 Thus, PI polyamide targeting of GPR56 using our compound is promising, useful, and safe for the treatment of EVI1high AML. | |||||
| 内容記述 | ||||||
| 以下に掲載: Scientific Reports .2018,Volume 8.Article number: 13741 (2018) | ||||||
| 学位名 | ||||||
| 学位名 | 博士(医学) | |||||
| 学位授与機関 | ||||||
| 学位授与機関識別子Scheme | kakenhi | |||||
| 学位授与機関識別子 | 17601 | |||||
| 学位授与機関名 | 宮崎大学 | |||||
| 学位授与年月日 | ||||||
| 学位授与年月日 | 2019-03-22 | |||||
| 学位授与番号 | ||||||
| 学位授与番号 | 甲第84号 | |||||
| 著者版フラグ | ||||||
| 出版タイプ | VoR | |||||
| 出版タイプResource | http://purl.org/coar/version/c_970fb48d4fbd8a85 | |||||
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Hasi, Rani Saha, n.d., GPR56の転写を阻害するピロール-イミダゾールポリアミドはEVIl高発現AMLの新規治療薬となる: Elsevier.
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