2014-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/645311摘要：背景急性骨髓性白血病 (acute myeloid leukemia, AML) 是一種骨髓細胞功能異常且癌症變化的疾病。因為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基因變異所導致。其中染色體的變異及基因的突變是重要的致病原因。基因的突變可分成三類 (一) 牽涉到細胞的過度增生及抗凋亡的基因：FLT3、RAS、KIT 及PTPN11等; (二) 影響到細胞分化調控的基因：CEBPA與RUNX1等；(三) 與epigenetics調控有關的基因。近年的研究也發現：骨髓微環境的調控也在急性骨髓性白血病的致癌過程中扮演重要角色。由於病患的臨床表現十分分歧，如何根據危險因子來做正確的評估及適當的治療是重要的議題。我們的團隊在以往的研究中已建立有關基因變異在急性骨髓性白血病病患的基因圖譜及整合性的預後評估系統。JAK2-STATs的訊息傳遞會調控細胞的生長、分化及凋亡，且不正常的活化與血液腫瘤的形成及惡化有關。其中細胞間素 (suppressors of cytokine signaling, SOCS1) 屬於JAK2-STATs訊息傳遞中重要的調控因子。SOCS1的不正常表現在固態腫瘤中會影響到腫瘤的擴散及轉移、血管的新生與病患的預後。在那些治療不佳的慢性骨髓性白血病病患中SOCS1的表現會異常增加。我們團隊也發現 SOCS1 基因的不正常甲基化會在急性骨髓性白血病病患中發生。種種顯示經由SOCS1的調控很可能在急性骨髓性白血病扮演著重要的角色，但目前尚無這方面的完整報告。研究方法:我們首先將探討SOCS1基因在急性骨髓性白血病患的臨床表現，與FAB分類、染色體變化及其他分子基因突變的關聯性，同時做有關治療效果與預後的分析。利用配對檢體 (診斷、緩解及復發時) 來觀察SOCS1 的表現，探討這些變化是否合適作為微量血癌細胞偵測的工具。最後將利用斑馬魚模式來進行有關調節SOCS1 表現及同時合併其他基因變異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 SOCS1 基因表現在急性骨髓性白血病的發生及進展中所扮演的角色，SOCS1 基因與其他基因突變的關連及其臨床上的重要性。若這些變異與預後有密切的相關，則可做為臨床上治療病患的重要參考，未來也有機會做為標靶治療的標的。<br> Abstract: Background and Aims:Acute myeloid leukemia (AML) is a relentless hematologic malignancy characterized by overproduction of myeloid blasts with suppression of normal hematopoiesis. Emerging evidences have shown that in addition to chromosomal changes, genetic and epigenetic alterations, microenvironment dysregulation may also play an important role in the development of AML.JAK-STATs are typically oncogenic through the constitutive activation of signal transduction pathway and inappropriate activation plays an important role in the formation of hematologic diseases, including AML. SOCS1 (suppressor of cytokine signaling 1) protein confers the function as negative regulator in signal transduction pathway. The function of SOCS1 in tumor cells is unclear and needed to be defined. SOCS1 was found to inhibit the growth of some solid cancers, such as prostate cancer cells and laryngeal carcinoma but it was also elevated in melanoma cancer cells and chronic myeloid leukemia. Our previous work showed that SOCS1 hypermethylation was detected in AML patients. These findings suggest that SOCS1 dysregulation may play an important role in human AML. However, to the best of our knowledge, there has been no comprehensive study to clarify the role of SOCS1 in AML yet in literature.Method:The SOCS1 gene expression will be analyzed by real-time quantitative PCR and gene methylation, by methylation specific polymerase chain reaction in leukemic cells from AML patients. SOCS1 expression will also be sequentially analyzed at remission and relapse to investigate its dynamic changes. Further analysis of its interaction with other genetic alterations will be done. The results will be correlated with the clinical features, FAB and WHO classifications, cytogenetics, and clinical outcome of the patients. Last, we will establish zebrafish models to investigate in vivo effects of SOCS1 expression alone, or with a second hit of other genetic alterations in leukemogenesis.Participatory Goal:From this study, we will know the role of SOCS1 expression in AML and its clinical implications. The interaction of SOCS1 expression with other genetic alterations will also be clarified. These results will be helpful to understand the pathogenesis of AML and identify the therapeutic implication of this alteration.SOCS1表現基因突變預後急性骨髓性白血病SOCS1 expressiongenetic alterationssurvivalacute myeloid leukemia (AML)