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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
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dc.contributor.advisor | 周文堅 (Wen-Chien Chou) | |
dc.contributor.author | Chien-Chin Lin | en |
dc.contributor.author | 林建嶔 | zh_TW |
dc.date.accessioned | 2021-06-15T16:12:04Z | - |
dc.date.available | 2021-02-23 | |
dc.date.copyright | 2021-02-23 | |
dc.date.issued | 2020 | |
dc.date.submitted | 2021-02-05 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/52331 | - |
dc.description.abstract | 急性骨髓性白血病是一個由血液前驅細胞所轉變成的癌症,是個進展快速且死亡率高的疾病;過去的研究指出具有白血病幹細胞特性者有更不好的預後。許多基因被報告與白血病幹細胞特性有關,其中一類很重要的是homeodomain家族的基因。HOPX是這家族中最小的一個蛋白,被發現在一些器官組織包括腸道、神經、肺泡、毛囊細胞是重要的幹細胞標記;也在許多實體癌症扮演抑癌基因的角色;然而其在造血系統的角色及功能尚不清楚。我們在研究的第一階段發現在急性骨髓性白血病的病人如果其白血病細胞的HOPX基因表現量高的人,其臨床特徵較具有白血病幹細胞特性以及靜止態特性。而為了探究HOPX在血液系統生理及病理上所扮演的角色,我們製造了一隻具有血液系統專一性Hopx基因剔除的小鼠(Hopx-/-)。這小鼠在年輕的時候,造血幹細胞在連續性的移植試驗會出現幹細胞再生能力下降的現象;進一步的轉錄組基因研究發現在年輕Hopx-/-小鼠的長期造血幹細胞會有'造血幹細胞基因印記特性'下降的情況。在18個月的時候,我們置放來長期觀察的六隻中有三隻出現'喪失造血幹細胞靜止特性的現象'。骨髓細胞的轉錄組基因分析發現Hopx-/-小鼠在Cxcl12-Cxcr4的這個徑路上有明顯的出現負調控的趨勢,而Cxcl12-Cxcr4的徑路對於維持造血幹細胞的靜止幹細胞特性目前已知扮演非常重要的角色。我們接著用MN1基因過度表達的方式去將小鼠的骨髓細胞轉化為急性骨髓性白血病細胞,如果是用Hopx-/-小鼠的造血細胞去轉化的,其表現型會較為侵襲性、分裂較快速,且Cxcl12-Cxcr4的這個徑路一樣是呈現負調控。於是我們進一步去測試病人的骨髓血漿CXCL12的濃度,發現到在低HOPX表現量的病人,其CXCL12的表現也較低。總結來說,我們的研究發現了HOPX在維持造血幹細胞靜止特性的重要,而且至少部分是經由CXCL12的路徑。 | zh_TW |
dc.description.abstract | Acute myeloid leukemia (AML) is a malignancy of hematopoietic stem/progenitor cells (HSPC) with high mortality rate. A high expression of leukemia stem cell (LSC) character in AML predics poor prognosis and several genes have been reported to be associated with leukemia stemness, including several homeodomain genes. Homeodomain-only protein homeobox (HOPX) is by far the smallest homeodomain protein. Recently, it has been regarded as a stem cell marker in intestine, hair follicles, and pulmonary alveolar cells. Studies also suggested roles of HOPX as a tumor suppressor gene in various solid cancers. However its roles in hematopoietic cells and hematologic malignancies remains largely unknown. We analyzed the expression levels extracted from the mRNA array data derived from 347 newly diagnosed de novo acute myeloid leukemia patient cohort in the National Taiwan University Hospital (NTUH) and found that patients with higher HOPX expression had a lower complete remission rate and shorter survival. The finding was validated in two independent cohorts. Multivariate analysis revealed that higher HOPX expression was an independent unfavorable prognostic factor irrespective of other known prognostic parameters and gene signatures derived from multiple cohorts. Gene set enrichment analysis showed higher HOPX expression was associated with both hematopoietic and leukemia stem cell signatures. While HOPX and HOX family genes showed concordant expression patterns in normal HSPC, their expression patterns and associated clinical and biological features were distinctive in acute myeloid leukemia settings, demonstrating HOPX as a unique homeobox gene.
To further explore the physiologic functions in hematopoietic system of HOPX, we generated a mouse model with hematopoietic cell-specific knockout of Hopx (Hopx-/-). In young Hopx-/- mice, the phenotypes were not distinct despite the transcriptomic study revealed decreased HSC signatures in long-term HSCs from the Hopx-/- mice. At 18 months of age, half of the Hopx-/- mice developed cytopenia and splenomegaly. Bone marrow (BM) from the sick mice showed phenotypes of loss of hematopoietic stem cell (HSC) quiescence. Transcriptomic study of the Hopx-/- marrow cells showed significant down-regulation of the Cxcl12-Cxcr4 axis, which is critical for maintenance of HSC quiescence. We next examined the role of Hopx in AML by using the MN1 overexpression murine leukemia model and found similar results. Furthermore, in human AML, BM plasma CXCL12 levels were lower in patients with lower HOPX expression. In summary, our study highlights the roles of Hopx in maintenance of quiescence of the hematopoietic stem cells through CXCL12 pathway in vivo and provides implication of this protein in normal and malignant hematopoiesis. | en |
dc.description.provenance | Made available in DSpace on 2021-06-15T16:12:04Z (GMT). No. of bitstreams: 1 U0001-0502202113474500.pdf: 4978219 bytes, checksum: b0dcfabb9c1e0a384beaaa2f009313c1 (MD5) Previous issue date: 2020 | en |
dc.description.tableofcontents | 目錄
中文摘要………………………………………………………………………………5 英文摘要………………………………………………………………………………6 博士論文內容 緒論(Introduction) ……..…………………………………………………8 急性骨髓性白血病簡介………………………………………………………….8 Homeodomain蛋白之文獻回顧………...……………………………………...10 Homeodomain蛋白……………………………………………………...10 HOX家族基因及蛋白…………………………………………………...11 HOX家族基因在造血系統的重要性………………………………...….12 HOX家族基因在造血系統的功能性研究……………............................12 HOX家族基因在急性骨髓性白血病上的角色之文獻回顧……………14 HOPX蛋白之文獻回顧………………………………..…...…………..............16 HOPX蛋白概論介紹………………….………………………………….16 HOPX在正常組織的分布………………….…………………………….17 HOPX在實體腫瘤的角色之文獻回顧…………………………………..20 研究材料與方法 (Materials and Methods) …………………..………….22 台大的急性骨髓性白血病微陣列資料庫……………………………………22 製造Hopx基因剔除小鼠…..………………………………………….………..22 叢集細胞株形成測定實驗(colony forming unit assay)………………..22 小鼠骨髓移植實驗……………………………………………………………23 MN1反轉錄病毒的轉導(transduction)…………………………………………23 病理切片以及免疫組織化學染色…………………………………………...…24 造血幹細胞的次世代基因定序………………………………………………24 酵素結合免疫吸附分析法(ELISA)測定CXCL12……………………………..24 結果(Results) ……………………………………………………………..25 HOPX基因與急性骨髓性白血病的臨床表徵關聯性…………………………25 HOPX基因與急性骨髓性白血病的預後相關性………………………………25 HOPX不同形式mRNA異構物的表達………………………………………27 HOPX與HOX家族基因在正常血球中的表現形態………………………...28 HOPX與HOX家族基因在急性骨髓性白血病中的表現形態………………29 HOPX與HOX有不同的造血幹細胞基因印記表現…………………………31 HOPX與HOX在急性骨髓性白血病的甲基化型態………………………32 年輕野生型小鼠與Hopx基因剔除型(Hopx-/-)小鼠之比較……………..33 年邁野生型小鼠與Hopx基因剔除型(Hopx-/-)小鼠之比較……………34 Hopx在MN1的致癌背景之下所扮演的角色………………………………37 CXCL12於急性骨髓性白血病患者骨髓血漿中的表現量…………………...38 討論(Discussion) …………………………………………………………39 生病小鼠表型之疾病鑑別診斷………………………………………………...40 生病小鼠之病理及機轉分析…………………………………………………...43 靜止幹細胞特性之相關討論…………………………………………………46 CXCL12路徑之相關討論………………………………………………………47 展望(Perspectives) ………………………………………………………....54 急性骨髓性白血病之治療現況及預後分類…………………………………54 白血病幹細胞對預後之影響及其標記的應用………………………………...55 HOPX與靜止態白血病細胞特性…………………………………..…………..55 HOPX與CXCL12-CXCR4……………………………………………………..56 參考文獻(References) ………………………………………………….…………...58 表目錄 表1、高及低HOPX表現量之急性骨髓性白血病病人的臨床表徵………………………………………………………………………………….67 表2、HOPX表現量與染色體變化之關係………………………………..……...68 表3、HOPX表現量與基因突變之關係……………………………………..…….69 表4、急性骨髓性白血病病人存活之單變項分析…………………………………..70 表5、急性骨髓性白血病病人存活之多變項分析……………………………….….72 表6、HOPX與其他已知基因組對急性骨髓性白血病預後之預測力……………………………………………………………………………………..73 表7、HOPX isoform的引子序列………………………..………………74 圖目錄 圖1、製造Hopx基因剔除小鼠…..………………………………………………..75 圖2、小鼠骨髓移植模式….….……………………………...……………………..76 圖3、不同HOPX isoform在急性骨髓性白血病病人的表達量……………….…77 圖4、HOPX在急性骨髓性白血病病人的甲基化表達量……………………..….78 圖5、HOPX以及HOX 基因在正常芽細胞以及急性骨髓性白血病細胞的表達量………………………………………………………………………………….….79 圖6、HOPX以及HOX 基因在不同血球細胞之表達量…………………...……80 圖7、HOPX以及HOX 基因在TCGA中RNAseq的絕對表現量…………..….81 圖8、HOPX以及HOX 基因在台大急性骨髓性白血病病人資料庫中臨床表徵之分布差異………………………….………………………………………………82 圖9、高低HOPX及HOX四組急性骨髓性白血病病人之存活差異…………..83 圖10、高低HOPX及HOX四組急性骨髓性白血病病人之臨床特徵及基因表現量差異……………………………………………………………………………….84 圖11、HOPX以及HOX 基因在急性骨髓性白血病病人之甲基化狀態分布差異……………………………………………………………………………………..85 圖12、十五個月大時小鼠之全血球數…………………………..………………..86 圖13、年輕小鼠間的骨髓血球細胞差異………………………………………....87 圖14、造血幹細胞內的次族群流式細胞儀標記圖……………………………....88 圖15、年輕小鼠骨髓細胞間的基因分布PCA分析……………………………..89 圖16、十八個月時的年邁小鼠表型分析…………………………………………90 圖17、年邁小鼠骨髓細胞間的基因分布PCA分析……………………………...92 圖18、年邁小鼠骨髓細胞間的轉錄體基因徑路分析……………………………93 圖19、年邁小鼠骨髓細胞間的基因分布PCA分析顯示功能性差異的路徑…...94 圖20、年邁小鼠骨髓細胞間的Cxcl12-Cxcr4路徑差異………………………....95 圖21、年邁小鼠骨髓細胞間的Cxcl12-Cxcr4路徑IPA分析……….…………...96 圖22、Hopx基因剔除小鼠的MN1白血病模式病理切片……………………....97 圖23、Hopx基因剔除小鼠的MN1白血病模式流式細胞儀分析……………....98 圖24、Hopx基因剔除小鼠的MN1白血病模式基因轉錄體分析…………...….99 圖25、急性骨髓性白血病病人之骨髓血漿CXCL12表達量…………………..100 附錄: 個人在修業期間所發表之論文清冊…………………………………101 | |
dc.language.iso | zh-TW | |
dc.title | 探討HOPX在血液系統及急性骨髓性白血病之角色 | zh_TW |
dc.title | Explore the role of HOPX in hematopoietic system and acute myeloid leukemia. | en |
dc.type | Thesis | |
dc.date.schoolyear | 109-1 | |
dc.description.degree | 博士 | |
dc.contributor.coadvisor | 田蕙芬(Hwei-Fang Tien) | |
dc.contributor.oralexamcommittee | 林亮音(Liang-in Lin),林家齊 (Chia-Chin Lin),蔡幸真(Hsing-Chen Tsai),劉俊煌(Jin-Hwang Liu),陳志丞(Chih-Cheng Chen) | |
dc.subject.keyword | HOPX,白血病幹細胞,靜止態,CXCL12,CXCR4, | zh_TW |
dc.subject.keyword | HOPX,leukemia stem cell,quiescence,CXCL12,CXCR4, | en |
dc.relation.page | 102 | |
dc.identifier.doi | 10.6342/NTU202100581 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2021-02-08 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 臨床醫學研究所 | zh_TW |
顯示於系所單位: | 臨床醫學研究所 |
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