BCL2 基因扩增缺失和转录重编程导致 B 细胞淋巴瘤模型对 ABT-199 耐药。
BCL2 Amplicon Loss and Transcriptional Remodeling Drives ABT-199 Resistance in B Cell Lymphoma Models.
机构信息
Chemical Biology and Molecular Medicine Program, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
出版信息
Cancer Cell. 2019 May 13;35(5):752-766.e9. doi: 10.1016/j.ccell.2019.04.005.
Abstract
Drug-tolerant "persister" tumor cells underlie emergence of drug-resistant clones and contribute to relapse and disease progression. Here we report that resistance to the BCL-2 targeting drug ABT-199 in models of mantle cell lymphoma and double-hit lymphoma evolves from outgrowth of persister clones displaying loss of 18q21 amplicons that harbor BCL2. Further, persister status is generated via adaptive super-enhancer remodeling that reprograms transcription and offers opportunities for overcoming ABT-199 resistance. Notably, pharmacoproteomic and pharmacogenomic screens revealed that persisters are vulnerable to inhibition of the transcriptional machinery and especially to inhibition of cyclin-dependent kinase 7 (CDK7), which is essential for the transcriptional reprogramming that drives and sustains ABT-199 resistance. Thus, transcription-targeting agents offer new approaches to disable drug resistance in B-cell lymphomas.
摘要
耐药“持久细胞”是肿瘤细胞，为耐药克隆的出现提供了基础，并导致肿瘤复发和疾病进展。在这里，我们报告称，套细胞淋巴瘤和双打击淋巴瘤模型中对 BCL-2 靶向药物 ABT-199 的耐药性是由失去携带 BCL2 的 18q21 扩增子的持久细胞克隆生长引起的。此外，通过适应性超级增强子重塑产生持久状态，该重塑重新编程转录，并为克服 ABT-199 耐药性提供了机会。值得注意的是，药物蛋白组学和药物基因组学筛选显示，持久细胞对转录机制抑制剂，特别是对细胞周期蛋白依赖性激酶 7（CDK7）抑制剂敏感，CDK7 是驱动和维持 ABT-199 耐药性的转录重编程所必需的。因此，转录靶向药物为治疗 B 细胞淋巴瘤的耐药性提供了新的方法。
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