Identification of BTK and BCL2 Inhibitors as Potential Combination Targeting of Apoptosis and Ferroptosis in Double-Hit Lymphoma

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題名:	Identification of BTK and BCL2 Inhibitors as Potential Combination Targeting of Apoptosis and Ferroptosis in Double-Hit Lymphoma
作者:	SETIAWAN, SYAHRU AGUNG
貢獻者:	國際醫學研究博士學位學程趙祖怡
關鍵詞:	Double-hit lymphoma;BTK;BCL2;ALOX5;Apoptosis;Ferroptosis
日期:	2023-06-19
上傳時間:	2023-12-07 09:56:08 (UTC+8)
摘要:	As the most aggressive subtype of Diffuse Large B-Cell Lymphoma (DLBCL), Double-Hit Lymphoma (DHL) has unfavorable prognoses with no viable therapeutic choices. The Bruton’s Tyrosine Kinase (BTK) is indispensable in regulating internal processes of neoplastic B cells. Genetic alteration of MYC with BCL2 or BCL6 renders dysfunctional apoptosis pathway, favoring targeting B-Cell Lymphoma 2 (BCL2). Considering targeting BTK or BCL2 signaling through inhibitors raises critical issues pertaining to resistance and side effects, disrupting these complementary pathways as a combination strategy seems reasonable. As recently identified iron-mediated cell death, ferroptosis has been implicated in BTK dysfunction, although the exact mechanism remains undefined. The main objective of this study is to determine the efficacy and synergism of BTK and BCL2 inhibitors in suppressing DHL. Additionally, typical marker that characterizes DHL features while capturing ferroptosis susceptibility would be determined. A comprehensive in silico approach was employed along with in vitro and in vivo validation using cell lines and clinical tissue specimens. BTK ablation decreased DHL proliferation and enhanced sensitivity to navitoclax. Combining second-generation BTK inhibitors with navitoclax suppressed DLBCL cells with a greater synergy in the DHL subset. The drug combination promoted apoptosis and ferroptosis distinctly. As ferroptosis triggered, reactive oxygen species (ROS) accumulation, lipid peroxidation, and reduction of glutathione were observed. BTK and BCL2 disruption triggered ferroptosis through NRF2, HMOX1, and GPX4 downregulation. Combination of zanubrutinib and navitoclax effectively inhibited DHL growth in vivo. RNA-sequencing of DLBCL tissue identified upregulation of ALOX5 in the DHL subset. ALOX5 overexpression was clinically associated with advanced disease and DHL subtype. B cell tumors consistently expressed ALOX5 along with BTK and BCL2. Additionally, significant correlations were observed between ALOX5 and sensivity to BTK or BCL2 inhibitors. Upregulation of ALOX5 in DHL cells indicates significant vulnerability to ferroptosis induction. In our study, zanubrutinib and navitoclax aggregated synergistically to suppress DHL through apoptosis and ferroptosis. ALOX5 linked double-hit lymphoma to ferroptosis vulnerability, suggesting this marker is potential to predict DHL patients who will benefit from ferroptosis-inducing drugs.
描述:	博士指導教授:趙祖怡委員:莊樹諄委員:葉淇臺委員:謝義興委員:黃奇英委員:趙祖怡
資料類型:	thesis
顯示於類別:	[國際醫學研究碩博士學位學程] 博碩士論文

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