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研究生：	陳雅萍 Chen, Ya-Ping
論文名稱：	以極光激酶作為急性淋巴性白血病的標的 Targeting Aurora Kinases in Acute Lymphoblastic Leukemia
指導教授：	陳彩雲 Chen, Tsai-Yun 洪良宜 Hung, Liang-Yi
學位類別：	博士 Doctor
系所名稱：	醫學院 - 臨床醫學研究所 Institute of Clinical Medicine
論文出版年：	2014
畢業學年度：	102
語文別：	英文
論文頁數：	138
中文關鍵詞：	急性淋巴性白血病、極光激酶、極光激酶抑制劑、MLL-AF4 、CDKN1A
外文關鍵詞：	ALL, Aurora kinases, Aurora kinase inhibitors, MLL-AF4, CDKN1A
相關次數：	點閱：113 下載：0
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雖然急性淋巴性白血病的治療成果已經獲得大幅改善，但是藥物抗藥性與疾病復發仍舊是急性淋巴性白血病需解決的難題。因此，目前仍有必要開發新的治療標的來克服這些困境。過去研究顯示極光激酶可能是某些癌症之治療標的。本研究主要探討極光激酶是否可以作為急性淋巴性白血病的治療標的。西方墨點法、逆轉錄聚合酶鏈式反應、免疫組織染色結果顯示，急性淋巴性白血病的細胞株與病患檢體具有高表現的極光激酶以及與臨床預後有關。極光激酶抑制劑VE-465 與VX-680在九株急性淋巴性白血病細胞株展現不同的藥物敏感性。急性淋巴性白血病對極光激酶抑制劑之藥物敏感性與極光激酶的表現量、磷酸化以及活化物無關。對極光激酶抑制劑藥物敏感之細胞株在藥物處理濃度於10–40 nM展現細胞凋亡以及表現極光激酶A被抑制之表型，然而對極光激酶抑制劑具有高抗藥性之細胞株在藥物處理濃度高於10 μM之下仍無法造成有效的抑制血癌細胞生長則表現極光激酶B被抑制之表型。進一步的研究顯示帶有MLL-AF4基因重組之細胞株與異種移植之老鼠模式顯示帶有MLL-AF4基因重組之急性淋巴性白血病對極光激酶抑制劑A (MLN8237) 具有相當好之抗癌效果，但是對極光激酶抑制劑B (ZM447439)則反應較差。進一步之分子機轉探討中發現CDKN1A在調控急性淋巴性白血病對極光激酶抑制劑之藥物反應是重要的分子之ㄧ，並且TP53的狀態並不會影響CDKN1A在調控急性淋巴性白血病對極光激酶抑制劑之抗癌效果。來自病人之MLL-AF4陽性之急性淋巴性白血病細胞具有高表現之CDKN1A且對極光激酶抑制劑有較佳之藥物敏感性。因此，本研究結果顯示CDKN1A可以做為生物指標以決定急性淋巴性白血病對極光激酶抑制劑之藥物反應，特別是在MLL-AF4陽性之急性淋巴性白血病之病患。

Despite improved treatment outcome in acute lymphoblastic leukemia (ALL), drug resistance and disease recurrence remain major obstacles in ALL. Thus, there is an urgent need to identify new targets for therapy. Several studies showed that Aurora kinases were potential therapeutic targets in some cancers. This study was aimed to investigate whether Aurora kinases would be the therapeutic targets in ALL. Aurora kinases were overexpressed in ALL cell lines and patient samples by Western blot, real-time quantitative PCR and immunohistochemistry and their expression pattern was associated with clinical outcomes. Pan-Aurora kinase inhibitors VE-465 and VX-680 exhibited different drug susceptibilities in nine ALL cell lines. Drug susceptibility of ALL cells was not correlated with the expression status of Aurora kinases, their phosphorylation or activators. Cells sensitive to Aurora kinase inhibitors underwent apoptosis at an IC50 around 10–40 nM and displayed a phenotype of Aurora-A inhibition, whereas cells resistant to Aurora kinase inhibitors (with an IC50 more than 10 μM) accumulated polyploidy, which resulted from Aurora-B inhibition. Furthermore, drug-sensitive MLL-AF4-positive cell lines and xenograft mice also had good anti-leukemia responses to specific Aurora-A inhibitors (MLN8237) but responded poorly to specific Aurora-B inhibitors (ZM447439). The further molecular mechanism demonstrated that CDKN1A played a critical role in governing the drug responsiveness of ALL in a TP53-independent manner. Primary MLL-AF4-positve ALL cells exhibiting high CDKN1A expression were sensitive to pan-Aurora kinase inhibitors. Therefore, our study suggested CDKN1A might serve as a potential biomarker in determining the drug responsiveness of Aurora kinase inhibitors in ALL, particularly in MLL-AF4-positive patients.

Abstract in Chinese                                  I
Abstract                                             II
Acknowledgment                                       III
Table of Content                                     IV
List of Figures                                      VIII
List of Tables                                       XI
List of Supplement                                   XII
List of Appendices                                   XIII
Abbreviations                                        XIV
Chapter 1: Introduction                              1	
1. Leukemia                                          1 
1-1. Acute lymphoblastic leukemia (ALL)              2	
1-2. Philadelphia chromosome-positive (Ph+) leukemia 3	
1-3. MLL-AF4-positive ALL	                            3	
2. Cell cycle regulation as a therapeutic target     4	
2-1. Cell cycle                                      4	
2-2. Aurora kinases                                  5	
2-3. Aurora kinases in cancer and leukemia	           7	
2-4. Aurora kinase inhibitors                        7	
3. Thesis aims                                       9	
4. Research significance                             10
Chapter 2: Materials and methods                     11	 I. Materials                                         11	
1. Chemical compound                                 11	
2. Primers used in this study                        15	
3. Gene knockdown                                    16	
4. Antibodies used in this study                     16
II. Methods                                          17	
1. Microarray analysis                               17	
2. Preparation of cell lysates and Western blot analysis 17
3. Immunohistochemical staining                      18 
4. Cell viability and proliferation assay            19
5. Xenograft model                                   19
6. Flow cytometry analysis                           19
7. Cell culture and transfection                     20 
8. RQ-PCR and semi-quantitative RT-PCR               21
9. Patients samples                                  21 
10. Sequencing of TP53 PCR products                  22
11. Statistical analysis                             23
Chapter 3: Results                                   24
Part I. The expression patterns of Aurora kinases in leukemia                                             24   
1. Aurora kinases were differently expressed in Ph+ leukemia (CML and ALL) cell lines and patient samples 24  
2. Aurora kinases were overexpressed in ALL cell lines and
 samples                                              25
3. The expression of Aurora-B was associated with higher
WBC counts and poor remission rate; Aurora-A in the nucleus 
was associated with unfavorable cytogenetics; the expression pattern of Aurora kinases would affect the clinical outcome			                    26
Part II. The treatment efficacy of Aurora kinase inhibitors 
in leukemia                                           28
1. Ph+ leukemia “CML and ALL cells” exhibited different drug susceptibility to Aurora kinase inhibitors       28
2. Aurora kinase inhibitors exhibited different drug 
susceptibility in ALL cell lines                      28
3. Aurora kinase inhibitors effectively inhibited the 
nocodazole-induced phosphorylation of Aurora kinases in  
drug-resistant and drug-sensitive ALL cells, not correlated with the IC50 of Aurora kinase inhibitors             29
4.	Drug-sensitive cell RS4;11 exhibited Aurora-A inhibition phenotypes but drug-resistant cell RPMI-8402 displayed Aurora-B inhibition phenotypes              29
5. Distinct expressions of apoptosis were observed in   
drug-sensitive cell RS4;11 and drug-resistant cell RPMI-8402 after exposure to Aurora kinase inhibitors       30
6. Aurora-A inhibitors expressed prominent anti-leukemia 
effects in RS4;11 but not Aurora-B inhibitors         30
7. Aurora-A inhibitors effectively inhibited the proliferation of MLL-AF4-positive ALL in human leukemia xenograft mouse Models				    31
Part-III. The molecular mechanism regulated the diverse    drug susceptibility of Aurora kinase inhibitors in ALL 32   
1. Aurora kinase inhibitors exhibited different drug 
susceptibility in ALL cell lines, not correlated with the 
expression level, phosphorylation status or activation status of Aurora kinases and the expression of MDR-1   32  
2. Aurora kinase inhibitors resulted in 165 gene changes in MLL-AF4-positive RS4;11, one of which was CDKN1A      32
3. Drug-sensitive ALL cells had higher baseline expressions of CDKN1A compared to drug-resistant ALL cells        33 
4. Aurora kinase inhibitors resulted in up-regulation of CDKN1A in drug-sensitive RS4;11 but no change of     
CDKN1A in drug-resistant RPMI-8402                    33
5. Knockdown of CDKN1A abrogated the anti-leukemic
effect of Aurora kinase inhibitors in drug-sensitive ALL 
cells “RS4;11”                                        34
6. Overexpression of CDKN1A enhanced the anti-leukemic
effect of Aurora kinase inhibitors in drug-resistant ALL cells		                                     35
7. There existed a TP53-indpendent CDKN1A signaling 
pathway regulating the drug susceptibility of Aurora kinase 
inhibitors                                            35
8. Primary de novo MLL-AF4-positive ALL cells 
exhibited high expressions of Aurora kinases and CDKN1A 
and were sensitive to Aurora kinase inhibitors        36
Chapter 4: Discussion                                 38
1. There is a link between CDKN1A and the drug
responsiveness of Aurora kinase inhibitors in ALL, 
especially in MLL-AF4-positive ALL                    38
2. Aurora kinases have prognostic roles in ALL        40
3. Different the various types of MLL-AF4 fusion transcripts do not have different drug responses to Aurora kinase inhibitors                                     41
4. TP53-indepdent CDKN1A signaling pathway plays an 
important role in mediating the drug responsiveness of Aurora kinase inhibitors in ALL                       41
5. Aurora-A is an important target for MLL-AF4-positive 
ALL		                                     42
6. There may be existence of other factors that regulate the expression of CDKN1A after exposure to Aurora kinases 
inhibitors                                            44
Chapter 5: Future Directions                          47
Chapter 6: References                                 48
Chapter 7: Figures                                    65
Chapter 8: Tables                                     98
Chapter 9: Supplement                                 109
Chapter 10: Appendices                                114
Chapter 11: Publications                              123
Chapter 12: Curriculum vitae                          126
                                    

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