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

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BCL2 Amplicon Loss and Transcriptional Remodeling Drives ABT-199 Resistance in B Cell Lymphoma Models.
Cancer Cell ( IF 48.8 ) Pub Date : 2019-05-13 , 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

Affiliation

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.
Department of Malignant Hematology, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
Department of Biostatistics and Bioinformatics, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
Department of Laboratory Medicine and Hematopathology, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
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.
Department of Cancer Physiology, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
BayCare Laboratories, LLC, Tampa, FL 33634, USA.
Department of Molecular Oncology, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
Department of Hematology, Tianjin Medical University General Hospital, Tianjin 300052, China.
Department of Hematology and Oncology, George Washington University, Washington, DC 20052, USA.
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68106, USA.
Lineberger Comprehensive Cancer Center, Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.
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.
Department of Tumor Biology, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
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.

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.

中文翻译：

BCL2扩增子丢失和转录重塑驱动B细胞淋巴瘤模型中的ABT-199抗性。

耐药的“持久性”肿瘤细胞是耐药克隆的出现的基础，并有助于复发和疾病进展。在这里，我们报告说，在套细胞淋巴瘤和双发淋巴瘤模型中，针对BCL-2靶向药物ABT-199的耐药性是由持久性克隆的生长演变而来，该克隆的丢失显示了带有BCL2的18q21扩增子。此外，持久性状态是通过自适应超级增强器重塑而产生的，该重塑体可以对转录进行重新编程，并为克服ABT-199耐药性提供了机会。值得注意的是，药代动力学和药物基因组学筛选显示，持久性分子容易受到转录机制的抑制，尤其是细胞周期蛋白依赖性激酶7（CDK7）的抑制，而后者对驱动和维持ABT-199抵抗的转录重编程至关重要。因此，

更新日期：2019-05-16

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