2010-08-012024-05-14https://scholars.lib.ntu.edu.tw/handle/123456789/660548摘要：染色體在複製的過程中，由於DNA 複製的方向性，使得染色體的端粒(telomere)需要端粒脢(telomerase)來彌補；否則，過短的端粒不僅會造成基因的不穩定也會造成染色體末端不正常結合，導致癌症的產生。骨髓性血液腫瘤，主要包括：骨髓增生性腫瘤(myelopoliferative neoplasm, MPN)、急性骨髓性白血病(acute myeloid leukemia, AML)、骨髓性發育不良症候群(myelodysplastic syndromes, MDS) 以及慢性骨髓性白血病(chronic myeloid leukemia,CML)。到目前為止，除了CML 以及AML 中的APL 族群有好的治療成效外，其餘病變的致病因子以及其相關的標靶治療的研究都需要關注。如同在先天性與後天性再生不良性貧血的病患中發現端粒脢相關蛋白與RNA 的基因變異造成骨髓不再增生，骨髓相關的疾病－骨髓性血液腫瘤(包括：MPN、MDS 與AML)在染色體端粒與端粒脢上也被發現有程度不一的不正常現象。但是骨髓性血液腫瘤基本上是骨髓增生的疾病與再生不良性貧血不同。可是不像再生不良性貧血有較完整的相關報告，骨髓性血液腫瘤的相關報告都不完整，有些只有端粒長度的報告，有些只有端粒脢的報告，有些只有相關基因的報告。一直以來，再生不良性貧血與MDS病患有一些程度的重疊，還有，再生不良性貧血、MDS 與MPN 都常有惡化成為AML的危機，可見這些疾病有彼此之間有一些關連性。因此，我們希望在此三年計劃中，就MPN、MDS 與AML 病患從各方面完整探討，包括染色體端粒長度以及端粒脢的活性、及其相關基因與表觀基因的分析；以期釐清這些生物標製作為診斷、追蹤以及評估預後的可能性。我們將在台大醫院倫理委員會的同意之下，在三年中探討AML、MDS以及MPN 病患至少各150 位的相關分析，作成至少三篇的績優論文。另一方面，對於端粒脢在骨髓性血液腫瘤中的調控機制並不清楚，也將藉此三年的計畫中作一個完整性的探討，包括；端粒脢基因hTERT 甲基化、組織蛋白乙醯化以及CCCTC‐binding factor(CTCF) 在調控轉錄作用上的機制探討。這些結果將有助於骨髓性血液腫瘤未來在作為診斷、追蹤以及評估預後的幫助外，也可以找出未來治療方法更新的標靶。<br> Abstract: During the DNA replication, telomere and telomerase are required to protect theshorter DNA stand; otherwise, the telomeres will become extremely short and dysfunctional;end‐to‐end fusions ultimately cause chromosomal instability, resulting in proliferation andcarcinogenesis.Myeloid malignancies include myelopoliferative neoplasm (MPN), acute myeloidleukemia (AML), myelodysplastic syndromes (MDS) and chronic myeloid leukemia (CML). Upto now, only patients with CML and AML with t(15;17) could be well cared with targettherapy, but others suffered from the side effect of chemotherapy again and again. Moretarget therapies are going to be developed underway.Congenital and acquired aplastic anemias (AA) were recently found to be associatedwith telomerase dysfunction, such as short telomere length, telomerase activity defect andthe associated gene (human telomerase reverse transcriptase, hTERT) mutation. However,some myeloid malignancy, such as MPN, MDS, and AML were found to have short telomerebut higher telomerase activity. These data were not complete for all series, even that someof them were found to have hTERT mutation, which is in contrary with the finding that highertelomerase activity in these disease. In addition, it has been report that patients with AA andMDS have some degree of similarity in phenotype; as well patients with AA, MDS and MPNhave predisposition to AML which is so‐called acute change. Therefore, in order to clarify thesignificance of telomere/telomerase machinery in myeloid malignancies, we will study therelated issues in at least 150 patients with MPN, MDS, and AML each, comprehensively inthese three years. The experiments we will carry out include the determination of telomerelength, telomerase activity assay, hTERT gene analysis, methylation analysis of hTERTpromoter. These data will be correlated with the cliniclpathological data for as significantbiomarkers. This clinical‐associated study will be carried out under the consent of theInstitutional Review Board of National Taiwan University Hospital. Those significantbiomarkers identified will serve as disease prediction and monitoring in the future. Theseresults will be reported to at least three articles published in outstanding journals.Regarding to the hTERT mutations newly identified in this study, we will carry out thebioinformatics investigation or perform the function assay of mutant hTERT to see if thesemutations are correlated with diseases.Furthermore, the regulation of hTERT at the transcription level in myeloid malignanciesis limited, epigenetic approach and the role of insulator CTCF in hTERT regulation will beclarified in this 3‐year study. Taken together, these results will contribute to emerging distinctbiomarkers and novel targets for future treatment.