ArticleCancer cell2019
BCL2 Amplicon Loss and Transcriptional Remodeling Drives ABT-199 Resistance in B Cell Lymphoma Models.
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Article in Cancer cell, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers.
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52 citing papers in PubMed, 80 citations in OpenAlex.
- Unc-51 like kinase 3 (ULK3) contributes to autophagy and cell survival in multiple myeloma.Nature communications · 2026Article
- Drug-tolerant persister cells in lymphoid malignancies: from mechanisms to therapeutic opportunities.Frontiers in oncology · 2026Review
- Drug-tolerant persister cells: the deadly survivors in hematological malignancies.Frontiers in pharmacology · 2026Review
- Transcriptional Condensates: Epigenetic Reprogramming and Therapeutic Targets in Hematologic Malignancies.Cancers · 2025Review
- Alantolactone Inhibits Double Expression Lymphoma via Dual-Targeted Glycogen Synthase Kinase 3 Beta and B-Cell Lymphoma2.Blood and lymphatic cancer : targets and therapy · 2025Article
- Predictors of response to venetoclax and therapeutic potential of CDK7 inhibition in multiple myeloma.Blood neoplasia · 2024Article
- Cancer drug-tolerant persister cells: from biological questions to clinical opportunities.Nature reviews. Cancer · 2024Review
- Drug tolerant persister cell plasticity in cancer: A revolutionary strategy for more effective anticancer therapies.Signal transduction and targeted therapy · 2024Review
- Venetoclax resistance leads to broad resistance to standard-of-care anti-MM agents, but not to immunotherapies.Blood advances · 2024Article
- Selective pharmacologic targeting of CTPS1 shows single-agent activity and synergizes with BCL2 inhibition in aggressive mantle cell lymphoma.Haematologica · 2024Article
- Identifying Targetable Vulnerabilities to Circumvent or Overcome Venetoclax Resistance in Diffuse Large B-Cell Lymphoma.Cancers · 2024Article
- Drug-tolerant persister cancer cells.Journal of the National Cancer Center · 2024Article
- Resistance to PRMT5-targeted therapy in mantle cell lymphoma.Blood advances · 2024Article
- Nomogram for predicting post-progression-free survival in patients with recurrent pancreatic ductal adenocarcinoma after radical surgery: a retrospective analysis.Frontiers in medicine · 2024Article
- CK1δ and CK1ε Signaling Sustains Mitochondrial Metabolism and Cell Survival in Multiple Myeloma.Cancer research · 2023Article
- Etiology of super-enhancer reprogramming and activation in cancer.Epigenetics & chromatin · 2023Review
- Immune-independent acquired resistance to PD-L1 antibody initiated by PD-L1 upregulation via PI3K/AKT signaling can be reversed by anlotinib.Cancer medicine · 2023Article
- Review
- MCL1 as a therapeutic vulnerability in Burkitt lymphoma.Leukemia · 2023Article
- Concurrent Inhibition of Akt and ERK Using TIC-10 Can Overcome Venetoclax Resistance in Mantle Cell Lymphoma.Cancers · 2023Article
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Authors and funding
32 authors at 9 institutions in 2 countries.
Xiaohong ZhaoChemical Biology and Molecular Medicine Program, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
Yuan RenChemical Biology and Molecular Medicine Program, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
Matthew LawlorDepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Bijal D ShahDepartment of Malignant Hematology, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
Paul M C ParkDepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Tint LwinChemical Biology and Molecular Medicine Program, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
Xuefeng WangDepartment of Biostatistics and Bioinformatics, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
Kenian LiuDepartment of Laboratory Medicine and Hematopathology, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
Michelle WangChemical Biology and Molecular Medicine Program, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
Jing GaoChemical Biology and Molecular Medicine Program, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
Tao LiChemical 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.
Mousheng XuDepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Ariosto S SilvaDepartment of Cancer Physiology, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
Kaplan LeeBayCare Laboratories, LLC, Tampa, FL 33634, USA.
Tinghu ZhangDepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
John M KoomenDepartment of Molecular Oncology, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
Huijuan JiangDepartment of Hematology, Tianjin Medical University General Hospital, Tianjin 300052, China.
Praneeth R SudalaguntaDepartment of Cancer Physiology, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
Mark B MeadsChemical Biology and Molecular Medicine Program, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
Fengdong ChengDepartment of Hematology and Oncology, George Washington University, Washington, DC 20052, USA.
Chengfeng BiDepartment of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68106, USA.
Kai FuDepartment of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68106, USA.
Huitao FanLineberger Comprehensive Cancer Center, Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.
William S DaltonDepartment of Malignant Hematology, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
Lynn C MoscinskiDepartment of Laboratory Medicine and Hematopathology, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
Kenneth H ShainDepartment of Malignant Hematology, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
Eduardo M SotomayorDepartment of Hematology and Oncology, George Washington University, Washington, DC 20052, USA.
Gang Greg WangLineberger Comprehensive Cancer Center, Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.
Nathanael S GrayDepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA 02215, USA.
John L ClevelandDepartment of Tumor Biology, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
Jun QiDepartment 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.
Jianguo TaoChemical 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.
Moffitt Cancer Center · USDana-Farber Cancer Institute · USGeorge Washington University · USHarvard University · USUniversity of Nebraska Medical Center · USUniversity of North Carolina at Chapel Hill · USBayCare Health System · USChinese Academy of Medical Sciences & Peking Union Medical College · CNTianjin Medical University General Hospital · CN
Funding
TRANSLATIONAL RESEARCHP30CA076292 · NCI · UNIVERSITY OF SOUTH FLORIDA · PI KENNETH Lynn WRIGHT · 1998 to 2026
$93.5MTYROSINE KINASE ONCOGENESIS IN MYELOID LEUKEMIAP01CA066996 · NCI · DANA-FARBER CANCER INSTITUTE · PI SCOTT A ARMSTRONG · 1996 to 2026
$52.5MTrageting the Multiple Myeloma EpigenomeP50CA100707 · NCI · DANA-FARBER CANCER INSTITUTE · PI ANDERSON, KENNETH C., MUNSHI, NIKHIL C. · 2003 to 2023
$45.0MTargeting Negative Regulatory Pathways for Immunotherapy of B-Cell LymphomasR01CA134807 · NCI · H. LEE MOFFITT CANCER CTR & RES INST · PI TAO, JIANGUO · 2010 to 2014
$2.3MCancer Epigenetics: A novel PRC2 Dysregulation Mechanism in Multiple MyelomaR01CA211336 · NCI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI WANG, G GREG · 2017 to 2021
$2.0MRole of Specific Histone Deacetylases in Lymphoma Immunobiology and TherapyR01CA179062 · NCI · H. LEE MOFFITT CANCER CTR & RES INST · PI SOTOMAYOR, EDUARDO M., TAO, JIANGUO · 2015 to 2019
$1.8MTageting BAFF and BAFF-Induced Non-Canonical NF-kB Pathways for Enhancing Mantle R01CA137123 · NCI · H. LEE MOFFITT CANCER CTR & RES INST · PI TAO, JIANGUO · 2009 to 2013
$1.3MEpigenetic Regulation of Drug Resistance to ABT-199 in B-cell MalignanciesR21CA234519 · NCI · H. LEE MOFFITT CANCER CTR & RES INST · PI CLEVELAND, JOHN L. · 2019 to 2020
$412kNCI NIH HHS P01 CA066996NCI NIH HHS P30 CA076292NCI NIH HHS P50 CA100707NCI NIH HHS R01 CA134807NCI NIH HHS R01 CA137123NCI NIH HHS R01 CA179062NCI NIH HHS R01 CA211336NCI NIH HHS R21 CA234519
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.
Indexed as
ABT-199BCL2CDK7double-hit lymphomadrug persisterdrug resistancemantle cell lymphomasuper-enhancer remodelingTHZ1transcriptome reprogramming
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