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研究生:楊文祺
研究生(外文):Wen-Chi Yang
論文名稱:BDH2及LCN2在染色體正常之急性骨髓性白血病之角色及臨床意義
論文名稱(外文):The role of BDH2 and LCN2 in cytogenetic normal acute myeloid leukemia and their clinical impacts
指導教授:林勝豐林勝豐引用關係
指導教授(外文):Sheng-Fung Lin
學位類別:博士
校院名稱:高雄醫學大學
系所名稱:醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2013
畢業學年度:101
語文別:中文
論文頁數:65
中文關鍵詞:染色體急性骨髓性白血病BDH2LCN2
外文關鍵詞:cytogenetic normalacute myeloid leukemiaBDH2LCN2
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在世界衛生組織(WHO)及歐洲白血病(European LeukemiaNet)分類對急性骨髓性白血病的診斷及評估預後上,已將許多分子標記如NPM1, FLT3及CEBPA列入固定評估標準之一,粒線體中的新陳代謝在癌症及正常細胞中的表現不同,一個新的存在於細胞質的物質BDH2 (cytosolic type type 2-hydroxybutyrate dehydrogenase,原來的命名為DHRS6),在細胞質中利用酮體,進而進入粒線體中進入TCA循環扮演重要的生理角色;在enterobactin 合成時,BDH2代謝2,3-DHBA的產物,並參與與24p3 (Liocalin 2, LCN2)相關的鐵質傳遞及細胞凋亡,LCN2與癌症的發生有關,在此篇論文,我們藉由分子醫學檢查,如定量及時性RT-PCR,來分析BDH2及LCN2與染色體正常的急性骨髓性白血病患者的預後,並一同分析是否與其他已知的分子標記如NPM1, FLT3及CEBPA,我們發現BDH2對染色體正常的急性骨髓性白血病患者是獨立的不良預後因子,表達量高的患者其存活較短且對治療反應較差,同時藉由BDH2降低表達的急性骨髓性白血病細胞株實驗,發現此現象是因BDH2扮演抗細胞凋亡的角色,且此反應是經由影響Survivin的表達,且BDH2的表達與細胞分化及細胞週期有關;LCN2被BDH2調控,其也與染色體正常的急性骨髓性白血病患者的預後相關,我們的結果顯示LCN2表達量高,尤其合併FLT3-ITD正常的病人,具較好的預後,在細胞株的實驗中,FLT3-ITD可中和掉在過氧化壓力下,LCN2高表達造成的細胞凋亡;在病人中,BDH2與LCN2的表達無相關。
結論:BDH2具抗氧化作用,為染色體正常的急性骨髓性白血病患者的不良預後因子,其下游因子LCN2則扮演一好的預後因子,尤其合併FLT3-ITD正常的情形。


Several molecular markers, such as NPM1, FLT3 and CEBPA have been incorporated into both the World Health Organization and European LeukemiaNet Classifications as routine assessments for the diagnosis and evaluation of prognostic significance in acute myeloid leukemia (AML). Mitochondrial metabolism is different between cancerous and normal cells. A novel cytosolic type 2-hydroxybutyrate dehydrogenase, BDH2, originally named DHRS6, plays a physiological role in the cytosolic utilization of ketone bodies, which can subsequently enter mitochondria and the tricarboxylic acid cycle. Moreover, BDH2 catalyzes the production of 2,3-DHBA during enterobactin biosynthesis and participates in 24p3 (Lipocalin2, LCN2)-mediated iron transport and apoptosis. LCN2 is related to cancer development. In the present study, we analyzed the prognostic effects and interactions of BDH2 and LCN2 expression (by molecular analysis, quantitative real-time polymerase chain reaction [qRT-PCR]) with neucleophosmin1, fms-related tyrosine kinase 3 (FLT3) and CCAAT/enhancer-binding protein alpha mutations in cytogenetic normal (CN)-AML patients receiving intensive induction chemotherapy. We observed that BDH2 expression is an independent poor prognostic factor for CN-AML. Patients with higher BDH2 expression have relatively shorter overall survival and low complete response rate. We also present that the effect of BDH2 on treatment response was based on its anti-apoptotic role, through inducible Survivin expression (by qRT-PCR and western blot) in BDH2 knock-down leukemia cell lines. Those cells also showed higher differentiation rate and cell cycle retardant. LCN2, regulated by BDH2, is related to prognosis inn CN-AML. Our results indicate that patients with higher LCN2 mRNA expression, especially in combination with wild type FLT3-ITD, had better prognoses. FLT3-ITD compensated LCN2-overexpression-enhanced oxidative stress induced apoptosis in cell line studies. There is no correlation between BDH2 and LCN2 mRNA expression in CN-AML patients'' bone marrow.
In conclusion, BDH2 is a novel poor prognostic predictor for CN-AML, with anti-apoptotic role. LCN2 play an important role, especially combined with FLT3-ITD wild type, as a good predictor in CN-AML patients.


   大   綱


中文摘要....................1
英文摘要....................2
前言......................3
前人研究.................... 4
研究材料及方法................. 6
研究結果....................15
討論......................48
結論......................53
將來方向....................54
參考論文....................55
附錄......................66


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