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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 田蕙芬 | zh_TW |
| dc.contributor.advisor | Hwei-Fang Tien | en |
| dc.contributor.author | 黃懷萱 | zh_TW |
| dc.contributor.author | Huai-Hsuan Huang | en |
| dc.date.accessioned | 2023-09-13T16:14:18Z | - |
| dc.date.available | 2023-11-09 | - |
| dc.date.copyright | 2023-09-13 | - |
| dc.date.issued | 2023 | - |
| dc.date.submitted | 2023-07-25 | - |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/89649 | - |
| dc.description.abstract | 背景資料
在細胞內的轉錄物（transcripts）裡，長鏈非編碼核糖核酸（Long non-coding RNAs，lncRNAs）佔了一大部分，也在造血作用（hematopoiesis）的過程中扮演重要角色。然而，長鏈非編碼核糖核酸對於血液惡性疾病，如：急性骨髓性白血病（acute myeloid leukemia，AML）和骨髓分化不良症候群（myelodysplastic syndrome，MDS），有何重要影響，目前所知有限。 在這個研究裡，我們研究的主角是HOXB-AS3，一個在人類HOXB 群組基因裡的長鏈非編碼核糖核酸；研究其在骨髓性細胞株裡的特性，及在急性骨髓性白血病患者和骨髓分化不良症候群患者裡，他們的臨床表徵及預後。 研究方法 我們利用短髮夾核糖核酸（short hairpin RNA，shRNA）去抑制HOXB-AS3在細胞株裡的表現，並觀察細胞生長情形，再使用微陣列（microarray）的方式，來分析及找尋細胞內被影響的基因，接著利用定量即時聚合酶鏈鎖反應（quantitative polymerase chain reaction）的方式來驗證。另外，我們也利用溴化去氧尿嘧啶流式細胞儀分析（BrdU flow assay），顯示HOXB-AS3對細胞生長分裂的影響。 更進一步地，我們回溯性研究HOXB-AS3，對於193位急性骨髓性白血病患者及157位骨髓分化不良症候群患者，其表現量與臨床表現及預後之影響。 研究結果 在急性骨髓性白血病細胞株OCI-AML3內，降低HOXB-AS3的表現，會抑制細胞的生長。在微陣列的分析中， HOXB-AS3不影響HOX基因的表現，反而會影響細胞周期及去氧核糖核酸複製相關的基因表現。 在急性骨髓性白血病患者裡，HOXB-AS3高表現的患者，其預後較低表現患者差（高表現者的整體存活期中位數為17.7 個月，相較於低表現者為未達到，P < 0.0001；高表現者的無復發存活期中位數為12.9 個月，相較於低表現者為未達到，P = 0.0070）。在骨髓分化不良症候群患者裡，也可看到類似狀況（高表現者的整體存活期中位數為14.6個月，相較於低表現者為42.4個月，P = 0.0018）。我們的分析結果，使用美國癌症基因體圖譜計畫急性骨髓性白血病患者群（TCGA AML cohort）及本院另外一組骨髓分化不良症候患者群，作為驗證組，也能重現。在骨髓分化不良症候群患者的次族群分析裡，在國際預後評分系統（international prognostic scoring system ，IPSS）低風險及中低風險的患者中，HOXB-AS3高表現能預測患者有較差的預後（高表現者的整體存活期中位數為29.2個月，相較於低表現者為77.3個月，P = 0.0194）；然而在高風險患者中，則無太大差異。 結論 本研究發現，HOXB-AS3在骨髓惡性疾病裡所扮演的角色，也進一步展現出，HOXB-AS3的表現量，對於急性骨髓性白血病患者及骨髓化不良症候群患者，在預後上的影響。 | zh_TW |
| dc.description.abstract | Background
Long non-coding RNAs (lncRNAs) represent the majority of cellular transcripts and play pivotal roles in hematopoiesis. However, their clinical relevance in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) remains largely unknown. Here, we investigated the functions of HOXB-AS3, a lncRNA located at human HOXB cluster, in the myeloid cells, and analyzed the prognostic significances in patients with AML and MDS. Methods We used shRNAs to downregulate lncRNA HOXB-AS3 in the cell lines, and then observed the cell growth. We investigated the downstream genes by microarray analysis, and validated the results with quantitative polymerase chain reaction. We also illustrated the effects of lncRNA HOXB-AS3 in the myeloid cell lines by BrdU proliferation flow assay. Further, we retrospectively analyzed lncRNA HOXB-AS3 expression in 193 patients with AML and 157 with MDS by microarray analysis and evaluated its clinical significance. Results Downregulation of lncRNA HOXB-AS3 suppressed cell proliferation in the myeloid cell line, OCI-AML3. In the microarray analysis, lncRNA HOXB-AS3 potentiated the expressions of several key factors in cell cycle progression and DNA replication without affecting the expressions of HOX genes. In AML, patients with higher HOXB-AS3 expression had shorter survival than those with lower HOXB-AS3 expression (median overall survival (OS), 17.7 months versus not reached, P<0.0001; median relapse-free survival, 12.9 months versus not reached, P=0.0070). In MDS, patients with higher HOXB-AS3 expression also had adverse prognosis compared with those with lower HOXB-AS3 expression (median OS, 14.6 months versus 42.4 months, P=0.0018). The prognostic significance of lncRNA HOXB-AS3 expression was validated in the TCGA AML cohort and another MDS cohort from our institute. The subgroup analyses in MDS patients showed that higher HOXB-AS3 expressions could predict poor prognosis only in low and low-intermediate IPSS risk groups (median OS, 29.2 months versus 77.3 months, P=0.0194), but not in high and intermediate-high IPSS risk groups. Conclusions This study uncovers a promoting role of lncRNA HOXB-AS3 in myeloid malignancies and identifies the prognostic value of lncRNA HOXB-AS3 expression in AML and MDS patients, particularly in the lower-risk group. | en |
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| dc.description.provenance | Made available in DSpace on 2023-09-13T16:14:18Z (GMT). No. of bitstreams: 0 | en |
| dc.description.tableofcontents | 口試委員會審定書 i
誌謝 ii 中文摘要 iii 英文摘要 v 目錄 vii 圖目錄 x 表目錄 xii 附圖目錄 xiii 附表目錄 xiv 縮寫及翻譯名稱列表 xv 第一章 研究背景 1 1.1 骨髓惡性疾病簡介 1 1.1.1 急性骨髓性白血病簡介 1 1.1.2 骨髓分化不良症候群簡介 2 1.1.3 小結 3 1.2 長鏈非編碼核糖核酸在骨髓惡性疾病裡的發現 3 1.2.1 長鏈非編碼核糖核酸簡介 3 1.2.2長鏈非編碼核糖核酸在急性骨髓性白血病裡所扮演的角色 4 1.3 HOX群組基因在急性骨髓性白血病之角色 5 1.4 研究目的 6 第二章 研究方法 7 2.1病患臨床相關資料收集與實驗 7 2.1.1研究案中收錄患者之選擇（Patient selection） 7 2.1.2染色體變化及基因突變之分析（Cytogenetic abnormalities and gene mutations） 8 2.1.3微陣列實驗及分析（Microarray experiments and analysis） 8 2.1.4 HOXB-AS3表現量與基因突變關係圖 9 2.2 細胞株相關實驗 9 2.2.1細胞株和細胞培養（Cell lines and cell cultures） 9 2.2.2短髮夾核糖核酸及長鏈非編碼核糖核酸之慢病毒載體設計及製造（Constructions of lentiviral vectors with shRNA and lncRNA, and lentiviral production） 10 2.2.3由慢病毒來製成穩定表現之細胞株（Lentivirus infection to generate stable cell lines） 11 2.2.4溴化去氧尿嘧啶流式細胞儀實驗（BrdU flow assay） 11 2.2.5細胞生長實驗（Proliferation assay） 12 2.2.6即時定量聚合酶連鎖反應（Real-time quantitative polymerase chain reaction，Q-PCR） 12 2.2.7核細胞質分離實驗（Nuclear-cytoplasm fractionation） 13 2.3統計分析（Statistical analysis） 14 第三章 研究結果Results 16 3.1 找尋與急性骨髓性白血病相關之長鏈非編碼核糖核酸 16 3.1.1 影響急性骨髓性白血病預後之長鏈非編碼核糖核酸 16 3.1.2 HOXB-AS3 在人類基因內的位置 16 3.1.3 HOXB-AS3為一跨物種且持續存在之基因 17 3.2 HOXB-AS3 在細胞內所扮演之角色 17 3.2.1 在骨髓性細胞株裡，抑制HOXB-AS3表現，會抑制細胞生長 17 3.2.2 HOXB-AS3 不影響HOX基因群的表現 18 3.2.3 HOXB-AS3對於細胞周期之影響與生長分裂相關基因之表現 18 3.2.4 HOXB-AS3 位在細胞質內為主 19 3.3 HOXB-AS3對於急性骨髓性白血病患者之重要性 20 3.3.1. HOXB-AS3在急性骨髓性白血病患者的表現及其臨床表徵 20 3.3.2. HOXB-AS3對急性骨髓性白血病患者的預後之影響 21 3.4 HOXB-AS3 對於骨髓分化不良症候群患者之重要性 22 3.4.1 HOXB-AS3 在骨髓分化不良症候群患者之表現 22 3.4.2骨髓分化不良症候群患者之臨床表徵 22 3.4.3 HOXB-AS3 對骨髓分化不良症候群患者之預後之影響 23 第四章 討論 25 4.1 HOXB-AS3在急性骨髓性白血病及骨髓分化不良症候群所扮演的角色 25 4.2 本研究之侷限 26 4.3 本研究發表後，其他HOXB-AS3相關研究之討論 27 4.4 長鏈非編碼核糖核酸將來可能的臨床應用 28 第五章結論 31 圖 32 表 70 參考文獻 78 附錄 83 附圖 83 附表 87 R語法 93 原始已發表之論文 95 修業期間發表之論文 96 | - |
| dc.language.iso | zh_TW | - |
| dc.subject | 急性骨髓性白血病 | zh_TW |
| dc.subject | 長鏈非編碼核糖核酸 | zh_TW |
| dc.subject | 骨髓分化不良症候群 | zh_TW |
| dc.subject | HOXB-AS3 | zh_TW |
| dc.subject | 細胞生長 | zh_TW |
| dc.subject | HOXB-AS3 | en |
| dc.subject | long non-coding RNA | en |
| dc.subject | myelodysplastic syndrome | en |
| dc.subject | acute myeloid leukemia | en |
| dc.subject | proliferation | en |
| dc.title | 長鏈非編碼核糖核酸HOXB-AS3在急性骨髓性白血病及骨髓分化不良症候群患者之角色 | zh_TW |
| dc.title | The role of long non-coding RNA HOXB-AS3 in patients with acute myeloid leukemia and myelodysplastic syndrome | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 111-2 | - |
| dc.description.degree | 博士 | - |
| dc.contributor.coadvisor | 陳瑞華;鄭安理 | zh_TW |
| dc.contributor.coadvisor | Ruey-Hwa Chen;Ann-Lii Cheng | en |
| dc.contributor.oralexamcommittee | 周文堅;林亮音;林國儀;周玉山 | zh_TW |
| dc.contributor.oralexamcommittee | Wen-Chien Chou;LIANG-IN LIN;Kuo-I Lin;Yuh-Shan Jou | en |
| dc.subject.keyword | HOXB-AS3,急性骨髓性白血病,骨髓分化不良症候群,長鏈非編碼核糖核酸,細胞生長, | zh_TW |
| dc.subject.keyword | HOXB-AS3,acute myeloid leukemia,myelodysplastic syndrome,long non-coding RNA,proliferation, | en |
| dc.relation.page | 99 | - |
| dc.identifier.doi | 10.6342/NTU202300729 | - |
| dc.rights.note | 同意授權(全球公開) | - |
| dc.date.accepted | 2023-07-26 | - |
| dc.contributor.author-college | 醫學院 | - |
| dc.contributor.author-dept | 轉譯醫學博士學位學程 | - |
| 顯示於系所單位： | 轉譯醫學博士學位學程 | |
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|---|---|---|---|
| ntu-111-2.pdf | 7.49 MB | Adobe PDF | 檢視/開啟 |
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