BCL2 Amplicon Loss and Transcriptional Remodeling Drives ABT-199 Resistance in B Cell Lymphoma Models PMID: 31085176

ADC Targets in Oncology

2026-04-10

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.

Xiaohong Zhao ¹ , Yuan Ren ¹ , Matthew Lawlor ² , Bijal D Shah ³ , Paul M C Park ² , Tint Lwin ¹ , Xuefeng Wang ⁴ , Kenian Liu ⁵ , Michelle Wang ¹ , Jing Gao ¹ , Tao Li ⁶ , Mousheng Xu ² , Ariosto S Silva ⁷ , Kaplan Lee ⁸ , Tinghu Zhang ² , John M Koomen ⁹ , Huijuan Jiang ¹⁰ , Praneeth R Sudalagunta ⁷ , Mark B Meads ¹ , Fengdong Cheng ¹¹ , Chengfeng Bi ¹² , Kai Fu ¹² , Huitao Fan ¹³ , William S Dalton ³ , Lynn C Moscinski ⁵ , Kenneth H Shain ³ , Eduardo M Sotomayor ¹¹ , Gang Greg Wang ¹³ , Nathanael S Gray ¹⁴ , John L Cleveland ¹⁵ , Jun Qi ¹⁶ , Jianguo Tao ¹⁷

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: [email protected].
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: [email protected].

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.