2012-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/645251摘要：背景:急性骨髓性白血病是一種骨髓細胞功能異常且癌症變化的疾病。因骨髓中缺乏正常的幹細胞，故無法製造足夠的正常血球。其致病的機轉被認為是多重機制，傳統上染色體的變異及基因的突變是重要的致病因；會牽涉到細胞的增生及存活及影響到細胞的分化調控。儘管如此，尚有20-30%的病患屬於正常染色體且無其他已知基因變化。我們之前的研究指出：除基因異常外，血管新生因子的增加及血管新生的改變在急性骨髓性白血病疾病的發生及轉移上扮演著重要的角色，然而這部分的致病機轉尚不明確。Enhancer of zeste homolog 2 (EZH2)屬於 polycomb group of genes (PcG)的一部分，它藉由與其他轉譯因子的互動，影響染色質單體修飾及染色質絲重組。同時扮演組蛋白甲基轉移酶的角色，藉由EZH2 失調會導致 G2-M 細胞週期基因的錯誤。近來發現可能在乳癌及攝護腺癌上扮演重要角色，也就是說EZH2表現的增加，會明顯造成腫瘤的生長，同時會縮短病患的存活率。此外有證據指出EZH2的表現與卵巢腫瘤的血管新生有密切相關，目前所知尚無針對EZH2的表現在急性骨髓性白血病人的具體研究。研究方法:在此項研究計畫中，我們首先將探討EZH2的表現在血癌細胞株及動物模式中對於血管新生表現的影響，繼而將系列的針對急性骨髓性白血病患在診斷時、緩解時、及復發時，EZH2 的表現，探討這些變化與臨床表現、微量血癌細胞偵測、FAB分類、染色體變化、其他分子基因突變及預後做相關性的分析。最後將利用移植鼠模式進行有關調節EZH2 表現合併其他基因突變在急性骨髓性白血病致癌機轉的研究。預期成果：這項研究將有助於了解急性骨髓性白血病病人EZH2的表現，同時在血癌細胞株與動物模式上驗證其與血管新生因子的影響。在臨床檢體的研究將可提供其與其他基因突變在癌化上的關聯，同時在移植鼠獲得表現型的驗證。最後，這些結果將有助於日後病患的追蹤及危險因子評估，甚而有助於選擇標靶藥物治療的重要參考。<br> Abstract: Background:Acute myeloid leukemia (AML) is a relentless hematologic malignancy characterized by overproduction of myeloid blasts with suppression of normal hematopoiesis. Somatically acquired mutation of critical gene, encoding key regulatory factors of cell function and transcription factors may play a role in the pathogenesis of AML. However, around 20-30% AML patients didn’t have such chromosomal abnormalities or known gene mutations. Emerging evidences have shown that in addition to chromosomal changes and gene alterations, angiogenesis may also play an important role in the development of AML.The enhancer of zeste homolog 2 (EZH2) is a member of the polycomb group of genes (PcG), which are important for transcriptional regulation through nucleosome modification, chromatin remodeling, and interaction with other transcription factors. It also showed that EZH2 serves as a histone methyl transferase (HMT), and disruption of EZH2 expression may lead to dysregulation of genes critical for the G2-M transition. Mounting evidences disclosed EZH2 expression was elevated in prostate and breast cancer and was closely associated with poor outcome. Recent study also demonstrated that EZH2 over-regulation contributed by angiogenesis regulation is crucial in ovary cancer development.Method:In this study, we will analyze EZH2 expression in leukemia cell lines and animal models to validate its association with tumor angiogenesis. Further, EZH2 expression in AML patients will be analyzed at diagnoses and sequentially during the follow-up to clarity its clinical significance. The results will be correlated with the clinical features, FAB and WHO classifications, cytogenetics, and clinical outcome of the patients. Furthermore, how such gene expression will cooperate with other genetic alterations in the leukemogenesis will also be investigated in transplantation mouse model.Participatory Goal:From this comprehensive study, we will know the role of EZH2 expression in AML and its interaction with other gene alterations in leukemogenesis. The results will be helpful to understand the pathogenesis of AML and identify the therapeutic implication of this alteration.DNMT3A基因突變原發性急性骨髓性白血病存活率生物標記復發