分化誘導劑增加慢性骨髓性白血病細胞K562對STI571誘導死亡的能力及其分子機制之探討

Differentiation-inducing Agents Sensitize Human Chronic Myeloid Leukemia Cell Line K562 to STI571-Induced Apoptosis and Their Molecular Mechanisms

黃郁雯(Yu-Wen Huang)

指導教授 ： 黃惠美

臺北醫學大學/醫學院/醫學科學研究所/碩士(2011年)

摘要

慢性骨髓性白血病 (Chronic Myeloid Leukemia, CML) 是一種異常的骨髓細胞增生症，屬於造血組織的惡性疾病之一，它是由於第9對與第22對染色體的轉位，形成 BCR/ABL chimeric 基因，製造出過度活化的BCR/ABL tyrosine kinase，此 BCR/ABL fusion protein 會促進血球幹細胞異常增生、抑制細胞凋亡及分化的命運。過去已經有研究發現 aclacinomycin A (ACM) 或 activin A會促進 K652 細胞紅血球系的分化；在本篇論文中，我們先利用ACM 及 activin A促進 K562 細胞分化後，再給予低劑量的 STI571 (200 nM, BCR/ABL inhibitor) 此種連續處理下與同時處理比較，連續處理能抑制 K652 細胞生長及誘導大量細胞進行凋亡。進一步實驗結果顯示，連續處理會透過活化caspase9、caspase3及 PARP cleavage 誘導 K562 細胞的凋亡；抑制 Mcl-1 ， Bcl-2 及 BCR/ABL蛋白質的表現，並且減少 Egr-1 及增加 p27 的表現。除此之外，在大量表現Egr-1 及 p38 dominant negative mutant 的穩定細胞株中給予連續處理下，也可發現分化程度及誘導細胞凋亡的現象被抑制。綜合以上研究顯示，慢性骨髓性白血病細胞經過分化後，會增加對 STI571 藥物的感受性，而促進細胞的凋亡。於未來治療慢性骨隨性白血病可提供為一種新的治療策略。

關鍵字

分化誘導劑；慢性骨髓性白血病；凋亡

並列摘要

Chronic myelogenous leukemia (CML) is characterized by the expression of the con-stitutively active BCR/ABL tyrosine kinase in hematopoietic stem cells. BCR/ABL induces the cell proliferation, apoptosis inhibition and differentiation arrest of CML cells. Previous studies showed that aclacinomycin A (ACM) and activin A induce the erythroid differentiation of human CML cell line K562. In this study, pretreating K562 cells with ACM or activin A followed by low-dose STI571 (200 nM, BCR/ABL inhibitor) show significant synergistic cytotoxicity compared with that of co-treatment. These results indicate that K562 cells are sensitized to low-dose STI571 by induction of erythroid differentiation. The sequential treatment of K562 cells with ACM or ac-tivin A followed by low-dose STI571 activated caspase9, caspase3 and PARP cleav-age and decreased the expression level of Mcl-1, Bcl-2 and BCR/ABL as well as down regulated Egr-1 and up-regulated p27 expression. Furthermore, overexpression of Egr-1 or p38 dominant negative mutant inhibited erythroid differentiation and re-duced the apoptosis of K562 cells in sequential treatment. Together, these results suggest that the sequential treatment of differentiation-inducing agents, ACM and activin A, and STI571 led to a synergistic increase in the apoptosis of K562 cells and may provide novel therapeutic strategy in CML.

並列關鍵字

Differentiation-inducing Agents；Chronic Myeloid Leukemia；Apoptosis

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