2011-05-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/645395摘要：背景：急性骨髓性白血病（簡稱AML）包括一群致病機轉、相異，對治療反應及預後亦不相同的惡性血液疾病。根據各個病人的危險因子選擇不同的治療對策（risk-adapted therapy），不但可以提高治療的效果，也可以減少不必要的副作用。一般認為AML的生成是由至少兩個或兩個以上的基因變異所引發，但最近的研究顯示表觀基因調控的異常，包括不正常的基因甲基化、組織蛋白（histone）修飾及微小RNA的表現，亦可能與AML的發生有關。在這兩年中，幾個與表現基因調控相關的基因突變陸續被發現，包括DNMT3A, TET2, EZH2, ASXL1及IDH1/2之變異等，更証明表觀基因體的異常在AML扮演相當重要的角色。我們過去一直致力於AML致病機轉的研究，包括幾個重要的基因突變，如AML1/RUNX1, WT1, CEBPA突變等, 而與表基因體修飾相關的基因ASXL1及IDH之突變大部分亦已完成；研究結果發現帶有這些基因突變的AML有其特殊的臨床表現及生物特性，且與病人的預後相關，可以與傳統影響病人預後的危險因子配合，做為調整治療策略的依據。同時我們亦發現某些特殊基因突變經常同時出現在同一個病人，顯示他們可能經由相互合作而致病。研究目的：探討與表觀基因修飾相關之基因突變在AML所扮演的角色及其臨床應用；以及這些突變與不正常之基因甲基化與微小RNA表現間的關聯性。研究方法：我們將對約500個AML病人在診斷時及後續的追踪過程中，檢測DNMT3A, TET2, EZH2等的突變，探討他們與臨床表現及病人預後間的關聯性，及分析這些突變與其他基因突變及表觀基因修飾異常的交互作用及影響性。與預後相關的變異將配合傳統的危險因子建立一個計分系統，以作為個人化醫療的依據；同時亦將在體外及老鼠模型觀察單一基因突變或兩個變異對細胞或老鼠的影響及對藥物的反應。預期成果：這項研究將有助於了解與表觀基因修飾相關之基因突變在AML所扮演的角色及臨床重要性。由所得結果可以將AML病人做更好的危險分級，並據以擬定治療策略。對於在AML進展中能維持穩定的變異，亦可做為病人治療後微量殘存疾病偵測的生物標記。在臨床上扮演重要角色的基因突變及其相關之表觀基因的異常，可以做為發展標靶治療的標的。而對目前AML眾多的基因異常，亦可設計一個檢測系統，提供病人例行快速的檢查。<br> Abstract: Background: Acute myeloid leukemia (AML) is a heterogeneous group of hematological malignancy with great variability in the pathogenesis, treatment response and clinical outcomes. Risk-adapted treatment may not only improve the survival of AML patients but also reduce the side effects from the treatment. The two-hit theory suggests that the development of AML requires the cooperation of at least two gene mutations. It is now recognized that epigenetic deregulation, such as aberrant DNA methylation, histone modification and microRNA expression, is another important mechanism in the pathogenesis of AML. In recent two years, mutations of genes that control epigenetic modifications, such as DNMT3A, TET2, EZH2, ASXL1, and IDH1/2, were detected in AML patients, further indicating an important role of abnormal epigenetic programming in the leukemogenesis. We have been devoted to the study of the pathogenesis of AML for many years, with special focus on several important gene mutations, including AML1/RUNX1, WT1, and CEBPA mutations etc. Furthermore, most of the work about ASXL1 and IDH mutations, which are also related to epigenetic deregulation, has been done. We find that AML with specific gene mutations has distinct clinical and biological characteristics. Some mutations are independent prognostic factors, so they can be integrated with conventional risk factors, such as age and cytogenetics, to better stratify AML patients for the most proper treatment. We also note frequently concomitant occurrence of certain gene mutations in the same individuals, suggesting a role of concerted interaction of these gene mutations in the pathogenesis of AML.Specific aims: To explore mutations of genes involving epigenetic modification and their clinical implications in AML patients and to investigate the correlation of these mutations with aberrant DNA methylation and microRNA expression.Methods: Mutations of DNMT3A, TET2, EZH2 and etc. will be performed in about 500 AML patients at diagnosis and during subsequent follow-ups. The clinical implications of these mutations and their association with other gene alterations and epigenetic abnormalities will be explored. In vitro cell manipulation and in vivo mouse models will be use to find out the effect of individual gene mutation alone or in combination on the cells or mice and the response to drugs.Anticipated results: From this study, the roles of gene mutations related to epigenetic deregulation and their clinical implications in AML will be known. A more sophisticated scoring system integrating molecular markers of prognostic significance with conventional risk factors can then be generated to better stratify AML patients for the most proper treatment. The mutations which are stable in AML progression can be used as biomarkers to monitor minimal residual disease after treatment. The mutations with clinical significance can be potential targets for the development of novel therapy. With so many gene alterations detected in AML till now, an array for direct hybridization capture and sequencing of the gene segments of interest can be developed for routine test, which may have the potential for commercialization.TET2突變急性骨髓性白血病TET2Acute myeloid leukemia