原名「台灣學術線上」
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項次 書目
1
題名:Molecular Genetics of Myeloid Leukemias: From Bench to Bedside    
骨髓性白血病的分子遺傳學:由實驗研究至臨床應用
著者:Lee-Yung Shih(施麗雲)
出版地區:台灣
出版城市:台北市
學科:醫學綜合
刊名:Journal of the Chinese Oncology Society
頁碼:1-35
語言:英語
摘要: 中文摘要PDF ; 英文摘要PDF

急性骨髓性白血病(AML)在基因學上變化多端,骨髓造血不良症候群(MDS)係一群單源性造血幹細胞疾患,經由多步驟分子生物病變,可惡化為急性骨髓性白血病。過去數年來,我們用全方位分子生物科技來(1)檢驗原發性急性骨髓性白血病core binding factor,RARα和MLL基因重組,並作微量偵測,(2)鑑認MLL融合拍檔基因,(3)分析骨髓性白血病之酪胺酸激?受體、Ras和造血轉錄因子基因的突變。 在急性骨髓性白血病,以反轉錄聚合?連鎖反應定出t(8;21)/AML1-ETO, inv(16)/CBFβ-MYH11,和t(15;17)/PML-RARα等的發生率。我們以南方墨點法篩檢MLL基因重組,以反轉錄聚合?連鎖反應檢測常見的MLL融合基因,以cDNA鍋柄式聚合?連鎖反應來鑑認不常見或不明的MLL拍檔基因。我們鑑認了兩個新的MLL融合基因(MLL-SEPT6和MLL-CBL),及兩個新的MLL-ENL斷裂點。MLL基因部份縱列複製在成人具MLL基因重組的急性骨髓性白血病是最常見的,而在兒童很少。我們分析具有PML-RARα或MLL基因重組的急性骨髓性白血病細胞,發現有高頻率的FLT3/Ras基因突變,可為引起急性骨髓性白血病發病的二次打擊模式的佐証。 AML1、CEBPα、PU.1是三種最重要的促成顆粒性白血球分化的轉錄因子。在骨髓造血不良症候群或轉化成急性骨髓性白血病病人,無PU.1基因突變,也少見CEBPα基因突變。而AML1基因突變在骨髓造血不良症候群或慢性骨髓單核球性白血病則常見。我們發表了全世界第一個兒童急性骨髓性白血病的CEBPα和FLT3-TKD基因突變論文。 我們也研究FLT3-ITD, FLT3-TKD, N-ras/K-ras,在急性骨髓性白血病復發時,及骨髓造血不良症候群轉化為急性骨髓性白血病時的角色。我們觀察到FLT3-ITD突變對一些急性骨髓性白血病病人病程的惡化扮演重要角色。而FLT3-TKD基因突變,在復發時型態多樣,表示這些突變是屬於次發性的變化。骨髓造血不良症候群病人在轉化成急性骨髓性白血病過程,有三分之一獲得FLT3或N-ras基因突變。骨髓造血不良症候群病人有FLT3-ITD者,預後差。兒童急性骨髓性白血病的FLT3-ITD比成人少,突變型與原型比值高的,預後差。 檢驗和監測這些基因異常和定量,已應用於診斷和治療。即時定量反轉錄聚合?連鎖反應用以偵測微量殘餘白血病,以界定是否達到分子緩解,並可偵知早期復發。將來,更多新的基因變異的研究和發現,可提供研發分子標靶治療,應用於臨床。
Acute myeloid leukemia (AML) is a genetically diverse hematologic malignancy. Myelodysplastic syndrome (MDS) refers to a group of clonal hematopoietic stem cell disorders which may progress to AML and involve a multistep molecular pathogenesis. In the past several years, we have used a full range of molecular technology, (1) to detect and monitor the most prognostically relevant fusion genes involving core binding factor, retinoic acid receptor α, and MLL rearrangements in AML, (2) to characterize the fusion partners of MLL gene, and (3) to analyze the mutations of receptor tyrosine kinase/Ras pathway and myeloid transcripts factors in myeloid leukemias. In AML, the frequencies of t(8;21)/AML1-ETO, inv(16)/CBFβ-MYH11, and t(15;17)/PML-RARα were defined by RT-PCR assays. We used Southern blot analysis to screen MLL rearrangement [MLL(+)] in de novo AML, RT-PCR to detect common MLL fusion transcripts and cDNA panhandle PCR to identify infrequent or unknown MLL partner genes. We identified two novel MLL fusion transcripts (MLL-SEPT6 and MLL-CBL) and 2 novel fusions of MLL-ENL. MLL-PTD was the most common genetic lesion in adult patients with MLL(+) AML, whereas MLL-PTD was rare in childhood AML. We also demonstrated that mutations in FLT3 or Ras genes were highly associated with AML harboring PML-RARα or MLL rearrangement, supporting the two-hit model of leukemogenesis. AML1, CEBPα and PU.1 are the three important myeloid transcription factors of granulopoiesis. Our results showed that CEBPα mutations were infrequent and PU.1 mutation was absent in patients with MDS/AML, whereas AML1 mutations were common in MDS or CMML. We have published the first pediatric AML series with CEBPα and FLT3/TKD mutations. The incidence of FLT3/ITD in childhood AML was lower than adult AML and a high ratio of mutant to wild-type FLT3 predicted poor prognosis. The roles of mutations of FLT3/ITD, FLT3/TKD, N-ras/K-ras and CEBPα genes in de novo AML at diagnosis and relapse, and in the transformation of AML from MDS were also examined. Nine percent of AML patients acquired FLT3/ITD mutations at relapse. We observed heterogeneous patterns, loss or gain, of FLT3/TKD mutations at AML relapse, suggesting the mutation being a secondary event in a subset of AML patients. One-third of MDS patients acquired FLT3 or N-ras mutations during AML evolution. FLT3/ITD was associated with a poor outcome in patients with MDS. Detection of the genetic abnormalities in AML have been translated into diagnostic approach and patient management. Characterization of novel genetic alterations will continue to provide a bench to bedside translation of molecularly targeted therapy in the future.




本卷期目次
Journal of the Chinese Oncology Society
Molecular Genetics of Myeloid Leukemias: From Bench to Bedside/ Lee-Yung Shih
Symptomatic Coronary Artery Diseases in Association with Thalidomide Therapy/ Yu-Chia LinWen-Chan TsaiHsueh-Wei YenLi-Tzong Chen
 
   
 
   

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