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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 林亮音(Liang-In Lin) | |
| dc.contributor.author | Tzu-Hsuan Chuang | en |
| dc.contributor.author | 莊子璇 | zh_TW |
| dc.date.accessioned | 2021-06-13T16:39:47Z | - |
| dc.date.available | 2014-10-07 | |
| dc.date.copyright | 2011-10-07 | |
| dc.date.issued | 2011 | |
| dc.date.submitted | 2011-07-18 | |
| dc.identifier.citation | 1. Dameshek W. Some speculations on the myeloproliferative syndromes. Blood. 1951 Apr;6(4):372-5.
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Ferraris AM, Pujic N, Mangerini R, Rapezzi D, Gallamini A, Racchi O, et al. Clonal granulocytes in polycythaemia vera and essential thrombocythaemia have shortened telomeres. Br J Haematol. 2005 Aug;130(3):391-3. 29. Ferraris AM, Mangerini R, Pujic N, Racchi O, Rapezzi D, Gallamini A, et al. High telomerase activity in granulocytes from clonal polycythemia vera and essential thrombocythemia. Blood. 2005 Mar 1;105(5):2138-40. 30. Bernard L, Belisle C, Mollica L, Provost S, Roy DC, Gilliland DG, et al. Telomere length is severely and similarly reduced in JAK2V617F-positive and -negative myeloproliferative neoplasms. Leukemia. 2009 Feb;23(2):287-91. 31. Cawthon RM. Telomere measurement by quantitative PCR. Nucleic Acids Res. 2002 May 15;30(10):e47. 32. Liu TC, Lin SF, Chang JG, Yang MY, Hung SY, Chang CS. Epigenetic alteration of the SOCS1 gene in chronic myeloid leukaemia. Br J Haematol. 2003 Nov;123(4):654-61. 33. Yoshikawa H, Matsubara K, Qian GS, Jackson P, Groopman JD, Manning JE, et al. SOCS-1, a negative regulator of the JAK/STAT pathway, is silenced by methylation in human hepatocellular carcinoma and shows growth-suppression activity. Nat Genet. 2001 May;28(1):29-35. 34. Blasco MA. Telomeres and human disease: ageing, cancer and beyond. Nat Rev Genet. 2005 Aug;6(8):611-22. 35. von Zglinicki T, Martin-Ruiz CM. Telomeres as biomarkers for ageing and age-related diseases. Curr Mol Med. 2005 Mar;5(2):197-203. 36. Verfaillie CM, Pera MF, Lansdorp PM. Stem cells: hype and reality. Hematology Am Soc Hematol Educ Program. 2002:369-91. 37. Lansdorp PM. Telomeres, stem cells, and hematology. Blood. 2008 Feb 15;111(4):1759-66. 38. Kim NW, Piatyszek MA, Prowse KR, Harley CB, West MD, Ho PL, et al. Specific association of human telomerase activity with immortal cells and cancer. Science. 1994 Dec 23;266(5193):2011-5. 39. Nawrot TS, Staessen JA, Holvoet P, Struijker-Boudier HA, Schiffers P, Van Bortel LM, et al. Telomere length and its associations with oxidized-LDL, carotid artery distensibility and smoking. Front Biosci (Elite Ed). 2010;2:1164-8. 40. Nordfjall K, Eliasson M, Stegmayr B, Melander O, Nilsson P, Roos G. Telomere length is associated with obesity parameters but with a gender difference. Obesity (Silver Spring). 2008 Dec;16(12):2682-9. 41. Starr JM, Shiels PG, Harris SE, Pattie A, Pearce MS, Relton CL, et al. Oxidative stress, telomere length and biomarkers of physical aging in a cohort aged 79 years from the 1932 Scottish Mental Survey. Mech Ageing Dev. 2008 Dec;129(12):745-51. 42. Capello D, Deambrogi C, Rossi D, Lischetti T, Piranda D, Cerri M, et al. Epigenetic inactivation of suppressors of cytokine signalling in Philadelphia-negative chronic myeloproliferative disorders. Br J Haematol. 2008 May;141(4):504-11. 43. Oh ST, Simonds EF, Jones C, Hale MB, Goltsev Y, Gibbs KD, Jr., et al. Novel mutations in the inhibitory adaptor protein LNK drive JAK-STAT signaling in patients with myeloproliferative neoplasms. Blood. 2010 Apr 19. 44. Delhommeau F, Dupont S, Della Valle V, James C, Trannoy S, Masse A, et al. Mutation in TET2 in myeloid cancers. N Engl J Med. 2009 May 28;360(22):2289-301. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/38629 | - |
| dc.description.abstract | 骨髓系增生疾病(Myeloproliferative neoplasms, MPNs)是骨髓系幹細胞發生異常變化使得下游的血液細胞發生過度增生所造成的一種疾病，典型的骨髓增生性疾病病人可分為真性紅血球增多症、血小板增多症和原發性骨髓纖維症。近年來有研究發現在細胞中負責保護染色體末端的端粒，其長度在骨髓增生性疾病病人中有明顯縮短的趨勢。我們藉由一對能結合至端粒重複序列的引子與一對能結合至單一基因(single copy gene)的引子，利用即時監控聚合酶連鎖反應的原理來測量各檢體的相對端粒長度--相對端粒長度(Relative telomere length)正比於端粒產物量(T)比上單一基因產物量(S)之比例(T/S ratio)。
我們分析63 位被測得有高於正常人血球數目的病人其端粒長度並與255 位測有正常血球數目的人做比較，再將此端粒長度的分析結果與其他骨髓增生性疾病突變檢測結果綜合評估。因為在正常人群組中，端粒長度會受個人的性別與年齡影響，因此這些因素在病人中亦被分別分析。 在63 位被測得有高於正常人血球數目的病人中有35 位為JAK2 V617F 陽性的病人。其中27 位V617F 陽性病人的端粒長度較同齡正常人有明顯縮短之現象。此外此端粒長度縮短的現象只有在病人的多核細胞檢體中被發現，在其單核細胞檢體中則否。而在不同性別的V617F 陽性病人比較中，女性病人與男性病人的端粒長度則沒有顯著的差異。在63 位被測得有高於正常人血球數目的病人中剩下的28 位為JAK2 V617F 陰性的病人，藉由甲基特異化聚合酶連鎖反應 (Methylation-specific PCR assay)的結果我們將V617F 陰性的病人分為在JAK2的抑制子SOCS3 promoter 有部份甲基化及無甲基化組。而在SOCS3 promoter有部份甲基化的四位病人中，都可發現其端粒長度都有較同齡正常人下降的表現。 因此實驗認為端粒長度分析可作為檢測JAK2V617F 陰性骨髓增生性疾病中於JAK2 的抑制子SOCS3 promoter 有部份甲基化的病人之另一項標的。 | zh_TW |
| dc.description.abstract | Myeloproliferative neoplasms (MPNs) are caused by several disorders of myeloid clonal stem cells and these diseases are characterized by chronic proliferation of hematopoietic precursors. There are three major types of classic myeloproliferative neoplasms: polycythemia vera (PV), essential thrombocytosis (ET), and primary myelofibrosis (PMF), and JAK2V617F is the most common biomarker to screen the patients with classic MPNs. Recent studies have reported that telomeres, which are complexes of tandem repeats and able to protect the chromosomes against homologous recombination and non-homologous end joining during cell division, showed significant shortening in patients with MPNs.
In this study, the quantitative-PCR assay measured the relative telomere length of 63 studied patients with abnormal increased leukocyte count, or increased platelet count, or increased hemoglobin level; and then the results of the patients was compared with 255 normal controls which have normal complete blood counts (the relative telomere length was the ratio of telomere product to single-copy gene product, T/S). Due to the telomere length was affected by different genders and ages in the normal control cohort, the comparisons of the patients between different genders and ages were processed separately. In the JAK2V617F-positive patient cohort, the results of paired comparisons showed that telomere lengths were remarkably shorter in 27 of 35 patients (27/35) than the age-matched normal controls. The telomere length shortening was observed mainly in the granulocytes but not in the mononuclear cells. Furthermore, no significant differences of telomere shortening were observed between female and maleJAK2V617F-positive patients. In addition, the mutation burden of JAK2V617F displayed no obvious correlation with telomere length shortening in the JAK2V617F-positive patient cohort. In the JAK2V617F-negative patients, abnormal SOCS3 promoter methylation pattern was found in four patients who had significantly shorter telomere lengths than their age-matched normal controls. SOCS3 promoter methylation has been reported among the patients with PMF in the previous reports, so these four SOCS3-positive patients with shorter telomere lengths could have primary myelofibrosis. In conclusion, this data suggested that telomere length analyses may support the diagnoses in patients with SOCS3 promoter methylation but without JAK2V617F. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-13T16:39:47Z (GMT). No. of bitstreams: 1 ntu-100-R97424009-1.pdf: 10304623 bytes, checksum: 6e0139ca09a6e91e9e01e55ab7b6996d (MD5) Previous issue date: 2011 | en |
| dc.description.tableofcontents | Acknowledgement 5
Abbreviation list 6 Chinese Abstract 7 English Abstract 8 I. Introduction 10 1.1 Myeloproliferative neoplasms 10 1.2 Janus kinase 2 and JAK2V617F 11 1.3 JAK2 exon12 mutations 12 1.4 JAK2 specific insertion segment mutations 12 1.5 Methylation status of SOCSs promoter 13 1.6 MPL W515L/K mutation 14 1.7 Telomere 14 1.8 Telomere length and myeloprolerative neoplasms 15 II. Aim 17 III. Materials and methods 18 3.1 Normal control cohort and studied patient cohort 18 3.2 Isolation of granulocytes and mononuclear cells 18 3.3 DNA samples extractions of buffy coat, granulocytes and lymphocytes 18 3.4 Real-time quantitative PCR assay for measuring telomere length 19 3.5 Statistical analysis 20 3.6 JAK2V617F analysis 20 3.7 JAK2 exon12 mutations analysis 21 3.8 JAK2 specific insertion segment sequencing 22 3.9 MPL W515L/K sequencing 22 3.10 Methylation status analysis of the promoter regions of SOCSs 23 3.11 HEL cell culture 24 IV. Results 25 4.1 Standard curves for telomere and the single copy gene 25 4.2 Telomere lengths in different genders, cell types and ages 25 4.3 The correlation of age and telomere length 27 4.4 Telomere length measurement in the JAK2V617F- positive patients 27 4.5 JAK2V617F burden and telomere lengths 30 4.6 Methylation status of SOCS promoters 30 4.7 Telomere length measurement in the JAK2V617F- negative patients 31 4.8 Other molecular abnormalities in the JAK2V617F- negative patients 32 V. Discussions 33 VI. Conclusion 37 VII.Figures 38 Figure 1 The amplification plot of telomeric and albumin products 38 Figure 2 The standard curves for telomere and albumin 39 Figure 3 Telomere lengths in different genders 40 Figure 4 Telomere lengths in different cell types 41 Figure 5 Correlation of relative T/S ratios and ages in the normal individuals 42 Figure 6 The telomere lengths in V617F-positive patients 43 Figure 7 The telomere lengths in patients with V617F- positive between different genders 44 Figure 8 The telomere lengths in V617F-positive patients compared with the age-matched normal controls 45 Figure 9 The V617F mutation burden shows no relationship with the telomere lengths 46 Figure 10 The methylation status analysis of SOCS3 promoter by MSP assay 48 Figure 11 The methylation status of SOCS1 promoter and SOCS1 exon2 region by MSP assay 49 Figure 12 The telomere lengths in the patients without V617F 50 VIII. Tables 51 Table 1 51 Table 2 52 Table 3 53 Table 4 54 IX. References 56 X. Supplementary Figures 61 Supplementary Figure 1 JAK-STAT pathway 61 Supplementary Figure 2 Mutations of JAK2 62 Supplementary Figure 3 The structure of telomere 63 Supplementary Figure 4 Design for telomere length measuring by Q-PCR 65 XI. Supplementary Tables 66 XII. Supplementary List 69 Supplementary List 1 69 Supplementary List 2 72 | |
| dc.language.iso | en | |
| dc.title | 骨髓系增生疾病病人之端粒長度之研究：俱潛力之診斷標的 | zh_TW |
| dc.title | Study on Telomere Length in Patients with Myeloproliferative
Neoplasms: A Potential Diagnostic Marker | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 99-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 呂健惠(Chien-Hui Lieu),楊雅倩(Ya-Chien Yang),顧雅真(Ya-Chen Ko),林淑萍(Su-Bin Lin) | |
| dc.subject.keyword | 骨髓系增生疾病,端粒, | zh_TW |
| dc.subject.keyword | Myeloproliferative Neoplasms,telomere Length, | en |
| dc.relation.page | 73 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2011-07-18 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 醫學檢驗暨生物技術學研究所 | zh_TW |
| 顯示於系所單位： | 醫學檢驗暨生物技術學系 | |
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