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

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 Sudalagunta; 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

doi:10.1016/j.ccell.2019.04.005

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

Cancer Cell. 2019 May 13;35(5):752-766.e9. doi: 10.1016/j.ccell.2019.04.005.

Authors

Xiaohong Zhao¹, Yuan Ren¹, Matthew Lawlor², Bijal D Shah³, Paul M C Park², Tint Lwin¹, Xuefeng Wang⁴, Kenian Liu⁵, Michelle Wang¹, Jing Gao¹, Tao Li⁶, Mousheng Xu², Ariosto S Silva⁷, Kaplan Lee⁸, Tinghu Zhang², John M Koomen⁹, Huijuan Jiang¹⁰, Praneeth R Sudalagunta⁷, Mark B Meads¹, Fengdong Cheng¹¹, Chengfeng Bi¹², Kai Fu¹², Huitao Fan¹³, William S Dalton³, Lynn C Moscinski⁵, Kenneth H Shain³, Eduardo M Sotomayor¹¹, Gang Greg Wang¹³, Nathanael S Gray¹⁴, John L Cleveland¹⁵, Jun Qi¹⁶, Jianguo Tao¹⁷

Affiliations

¹ Chemical Biology and Molecular Medicine Program, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
² Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
³ Department of Malignant Hematology, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
⁴ Department of Biostatistics and Bioinformatics, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
⁵ Department of Laboratory Medicine and Hematopathology, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
⁶ Chemical Biology and Molecular Medicine Program, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of VIP Medical Services, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
⁷ Department of Cancer Physiology, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
⁸ BayCare Laboratories, LLC, Tampa, FL 33634, USA.
⁹ Department of Molecular Oncology, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
¹⁰ Department of Hematology, Tianjin Medical University General Hospital, Tianjin 300052, China.
¹¹ Department of Hematology and Oncology, George Washington University, Washington, DC 20052, USA.
¹² Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68106, USA.
¹³ Lineberger Comprehensive Cancer Center, Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.
¹⁴ Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA 02215, USA.
¹⁵ Department of Tumor Biology, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
¹⁶ Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02215, USA. Electronic address: jun_qi@dfci.harvard.edu.
¹⁷ Chemical Biology and Molecular Medicine Program, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Laboratory Medicine and Hematopathology, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. Electronic address: jianguo.tao@moffitt.org.

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.

Keywords: ABT-199; BCL2; CDK7; THZ1; double-hit lymphoma; drug persister; drug resistance; mantle cell lymphoma; super-enhancer remodeling; transcriptome reprogramming.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

Abstract

Publication types

Grants and funding