Endemic Burkitt lymphoma avatar mouse models for exploring inter-patient tumor variation and testing targeted therapies.
Endemic Burkitt lymphoma avatar mouse models for exploring inter-patient tumor variation and testing targeted therapies.
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DOI：
10.26508/lsa.202101355
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发表时间：
2023-05
影响因子：
4.4
通讯作者：
Ong'echa, John M.
中科院分区：
文献类型：
--
作者：
Lakshmi, Priya Saikumar;Oduor, Cliff, I;Forconi, Catherine S.;Bana, Viriato M. ';Bly, Courtney;Gerstein, Rachel M.;Otieno, Juliana A.;Muenz, Christian;Luftig, Micah A.;Brehm, Michael A.;Bailey, Jeffrey A.;Moormann, Ann M.;Ong'echa, John M.
患者来源的肿瘤模型在评估新的癌症治疗方法方面显示出希望，这些治疗方法可以改善被诊断为EBV相关地方性Burkitt淋巴瘤的非洲儿童的预后。地方性Burkitt淋巴瘤是撒哈拉以南非洲的一种儿童癌症，以Epstein-Barr病毒和疟疾相关的异常B细胞激活和MYC染色体易位为特征。常规化疗后存活率徘徊在50%；因此，临床相关模型是必要的，以测试额外的治疗方法。因此，我们建立了5个患者来源的BL肿瘤细胞系和相应的NSG-BL替身小鼠模型。转录学证实，我们的BL线保持了从患者肿瘤到NSG-BL瘤的保真度。然而，我们发现NSG-BL化身之间的肿瘤生长和存活率以及Epstein-Barr病毒蛋白的表达模式存在显著差异。我们测试了利妥昔单抗的反应性，发现一个NSG-BL模型表现出直接的敏感性，其特征是凋亡基因的表达被未折叠的蛋白反应和mTOR促进生存的途径所抵消。在利妥昔单抗无反应的肿瘤中，我们观察到干扰素-α的特征被IRF7和ISG15的表达所证实。我们的结果显示了患者间显著的肿瘤变异和异质性，当代患者来源的BL细胞系和NSG-BL替身是指导新的治疗策略和改善这些儿童预后的可行工具。
Patient-derived tumor models show promise for evaluating novel cancer treatments that could improve outcomes for African children diagnosed with EBV-associated endemic Burkitt lymphoma. Endemic Burkitt lymphoma (BL) is a childhood cancer in sub-Saharan Africa characterized by Epstein–Barr virus and malaria-associated aberrant B-cell activation and MYC chromosomal translocation. Survival rates hover at 50% after conventional chemotherapies; therefore, clinically relevant models are necessary to test additional therapies. Hence, we established five patient-derived BL tumor cell lines and corresponding NSG-BL avatar mouse models. Transcriptomics confirmed that our BL lines maintained fidelity from patient tumors to NSG-BL tumors. However, we found significant variation in tumor growth and survival among NSG-BL avatars and in Epstein–Barr virus protein expression patterns. We tested rituximab responsiveness and found one NSG-BL model exhibiting direct sensitivity, characterized by apoptotic gene expression counterbalanced by unfolded protein response and mTOR pro-survival pathways. In rituximab-unresponsive tumors, we observed an IFN-α signature confirmed by the expression of IRF7 and ISG15. Our results demonstrate significant inter-patient tumor variation and heterogeneity, and that contemporary patient-derived BL cell lines and NSG-BL avatars are feasible tools to guide new therapeutic strategies and improve outcomes for these children.
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影响因子：
4.3
作者：
Kanakry, Jennifer A.;Ambinder, Richard F.
通讯作者：
Ambinder, Richard F.
DOI：
10.1158/1541-7786.mcr-16-0305
发表时间：
2017-05
期刊：
Molecular cancer research : MCR
影响因子：
--
作者：
Kaymaz Y;Oduor CI;Yu H;Otieno JA;Ong'echa JM;Moormann AM;Bailey JA
通讯作者：
Bailey JA
影响因子：
29
作者：
Guo, Rui;Liang, Jin Hua;Zhang, Yuchen;Lutchenkov, Michael;Li, Zhixuan;Wang, Yin;Trujillo-Alonso, Vicenta;Puri, Rishi;Giulino-Roth, Lisa;Gewurz, Benjamin E.
通讯作者：
Gewurz, Benjamin E.
DOI：
10.1073/pnas.1705301114
发表时间：
2017-11-07
影响因子：
11.1
作者：
Herndler-Brandstetter, Dietmar;Shan, Liang;Flavell, Richard A.
通讯作者：
Flavell, Richard A.
影响因子：
12.4
作者：
Fitzsimmons, Leah;Boyce, Andrew J.;Rowe, Martin
通讯作者：
Rowe, Martin