BCL2 Amplicon Loss and Transcriptional Remodeling Drives ABT-199 Resistance in B Cell Lymphoma Models

• DOI: 10.1016/j.ccell.2019.04.005
• Publication Date: 2019-05-13T14:32:54Z
• Authors: Xiaohong Zhao; Yuan Ren; Matthew Lawlor; Bijal D. Shah; Paul M.C. Park; Tint Lwin; Xuefeng Wang; Kenian Liu; Michelle Wang; Jing Gao; Tao Li; Mousheng Xu; Ariosto S. Silva; Kaplan Lee; Tinghu Zhang; John M. Koomen; Huijuan Jiang; Praneeth R. Sudal...; Mark B. Meads; Fengdong Cheng; Chengfeng Bi; Kai Fu; Huitao Fan; William S. Dalton; Lynn C. Moscinski; Kenneth H. Shain; Eduardo M. Sotomayor; Gang Greg Wang; Nathanael S. Gray; John L. Cleveland; Jun Qi; Jianguo Tao
• Keywords: Amplicon

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.