BCL2 Amplicon Loss and Transcriptional Remodeling Drives ABT-199 Resistance in B Cell Lymphoma Models
| Autor: | Lynn C. Moscinski, Huijuan Jiang, Fengdong Cheng, Nathanael S. Gray, Matthew A. Lawlor, Paul M.C. Park, John M. Koomen, Jianguo Tao, William S. Dalton, Bijal D. Shah, Michelle Wang, John L. Cleveland, Chengfeng Bi, Jing Gao, Xuefeng Wang, Kaplan Lee, Kenneth H. Shain, Tint Lwin, Mousheng Xu, Kai Fu, Kenian Liu, Tao Li, Huitao Fan, Yuan Ren, Praneeth Reddy Sudalagunta, Jun Qi, Xiaohong Zhao, Gang Greg Wang, Eduardo M. Sotomayor, Tinghu Zhang, Ariosto S. Silva, Mark B. Meads |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Cancer Research Kinase Cell Biology Drug resistance Biology Amplicon medicine.disease Article Lymphoma 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Oncology 030220 oncology & carcinogenesis medicine Cancer research Mantle cell lymphoma Cyclin-dependent kinase 7 B-cell lymphoma Reprogramming |
| Zdroj: | Cancer Cell. 35:752-766.e9 |
| ISSN: | 1535-6108 |
| Popis: | Summary 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. |
| Databáze: | OpenAIRE |
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