Evidence map›Paper›PMID 35704690›Full record

ArticleBlood2022

Deregulation and epigenetic modification of BCL2-family genes cause resistance to venetoclax in hematologic malignancies.

D Thomalla, L Beckmann, C Grimm, M Oliverio, L Meder, C D Herling, P Nieper, T Feldmann, O Merkel, E Lorsy and 27 more

Open access · hybridAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Blood, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 69 papers.

0numbers the graph read from it
0cells of the map it votes in
69citing papers in PubMed
17.7field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

69 citing papers in PubMed, 120 citations in OpenAlex.

  1. Trial
  2. Nucleolin Alterations and ROS Production Associate With Sensitivity of AML Cells to Venetoclax.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026
    Article
  3. Review
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  5. Targeting cellular senescence alleviates bone marrow aging.bioRxiv : the preprint server for biology · 2026
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9 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

37 authors at 5 institutions in 1 country.

D ThomallaFaculty of Medicine and Cologne University Hospital, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany.
L BeckmannFaculty of Medicine and Cologne University Hospital, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany.ORCID 0000-0001-5207-8991
C GrimmInstitute for Translational Epigenetics, Medical Faculty, University of Cologne, Cologne, Germany.ORCID 0000-0002-4676-8870
M OliverioFaculty of Medicine and Cologne University Hospital, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany.ORCID 0000-0002-7969-2796
L MederFaculty of Medicine and Cologne University Hospital, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany.
C D HerlingFaculty of Medicine and Cologne University Hospital, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany.
P NieperFaculty of Medicine and Cologne University Hospital, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany.
T FeldmannInstitute for Translational Epigenetics, Medical Faculty, University of Cologne, Cologne, Germany.
O MerkelFaculty of Medicine and Cologne University Hospital, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany.
E LorsyFaculty of Medicine and Cologne University Hospital, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany.
A da Palma GuerreiroFaculty of Medicine and Cologne University Hospital, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany.
J von JanFaculty of Medicine and Cologne University Hospital, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany.
I KisisFaculty of Medicine and Cologne University Hospital, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany.ORCID 0000-0001-6207-3991
E WasserburgerInstitute for Translational Epigenetics, Medical Faculty, University of Cologne, Cologne, Germany.
J ClaasenFaculty of Medicine and Cologne University Hospital, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany.
E Faitschuk-MeyerMiltenyi Biotec B.V. & Co. KG, Bergisch-Gladbach, Germany.
J AltmüllerCologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.ORCID 0000-0003-4372-1521
P NürnbergCologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.ORCID 0000-0002-7228-428X
T-P YangCenter for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
M LienhardDepartment of Computational Molecular Biology, Max-Planck-Institute for Molecular Genetics, Berlin, Germany.ORCID 0000-0002-2549-3142
R HerwigDepartment of Computational Molecular Biology, Max-Planck-Institute for Molecular Genetics, Berlin, Germany.ORCID 0000-0002-9335-1760
K-A KreuzerFaculty of Medicine and Cologne University Hospital, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany.
C P PallaschFaculty of Medicine and Cologne University Hospital, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany.
R BüttnerDepartment of Pathology, University of Cologne, Cologne, Germany.
S C SchäferDepartment of Pathology, University of Cologne, Cologne, Germany.ORCID 0000-0002-2116-1212
J HartleyRCI, Regensburg Center for Interventional Immunology, University Hospital of Regensburg, Regensburg, Germany.
H AbkenRCI, Regensburg Center for Interventional Immunology, University Hospital of Regensburg, Regensburg, Germany.ORCID 0000-0002-4302-3240
M PeiferCenter for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.ORCID 0000-0002-5243-5503
H KashkarCologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
G KnittelDepartment of Hematology and Stem Cell Transplantation, University Hospital Essen, University Duisburg-Essen, German Cancer Consortium (DKTK Partner Site Essen), Essen, Germany.ORCID 0000-0001-8395-3701
B EichhorstFaculty of Medicine and Cologne University Hospital, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany.
R T UllrichFaculty of Medicine and Cologne University Hospital, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany.
M HerlingFaculty of Medicine and Cologne University Hospital, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany.
H C ReinhardtDepartment of Hematology and Stem Cell Transplantation, University Hospital Essen, University Duisburg-Essen, German Cancer Consortium (DKTK Partner Site Essen), Essen, Germany.
M HallekFaculty of Medicine and Cologne University Hospital, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany.
M R SchweigerInstitute for Translational Epigenetics, Medical Faculty, University of Cologne, Cologne, Germany.
L P FrenzelFaculty of Medicine and Cologne University Hospital, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany.
University of Cologne · DEEssen University Hospital · DEMax Planck Institute for Molecular Genetics · DEUniversity Hospital Regensburg · DEMiltenyi Biotec (Germany) · DE

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

The BCL2 inhibitor venetoclax has been approved to treat different hematological malignancies. Because there is no common genetic alteration causing resistance to venetoclax in chronic lymphocytic leukemia (CLL) and B-cell lymphoma, we asked if epigenetic events might be involved in venetoclax resistance. Therefore, we employed whole-exome sequencing, methylated DNA immunoprecipitation sequencing, and genome-wide clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 screening to investigate venetoclax resistance in aggressive lymphoma and high-risk CLL patients. We identified a regulatory CpG island within the PUMA promoter that is methylated upon venetoclax treatment, mediating PUMA downregulation on transcript and protein level. PUMA expression and sensitivity toward venetoclax can be restored by inhibition of methyltransferases. We can demonstrate that loss of PUMA results in metabolic reprogramming with higher oxidative phosphorylation and adenosine triphosphate production, resembling the metabolic phenotype that is seen upon venetoclax resistance. Although PUMA loss is specific for acquired venetoclax resistance but not for acquired MCL1 resistance and is not seen in CLL patients after chemotherapy-resistance, BAX is essential for sensitivity toward both venetoclax and MCL1 inhibition. As we found loss of BAX in Richter's syndrome patients after venetoclax failure, we defined BAX-mediated apoptosis to be critical for drug resistance but not for disease progression of CLL into aggressive diffuse large B-cell lymphoma in vivo. A compound screen revealed TRAIL-mediated apoptosis as a target to overcome BAX deficiency. Furthermore, antibody or CAR T cells eliminated venetoclax resistant lymphoma cells, paving a clinically applicable way to overcome venetoclax resistance.

Indexed as

Hematologic NeoplasmsLeukemia, Lymphocytic, Chronic, B-CellLymphoma, Large B-Cell, DiffuseApoptosis Regulatory Proteinsbcl-2-Associated X ProteinBridged Bicyclo Compounds, HeterocyclicDrug Resistance, NeoplasmEpigenesis, GeneticHumansMyeloid Cell Leukemia Sequence 1 ProteinProto-Oncogene Proteins c-bcl-2SulfonamidesApoptosis Regulatory Proteinsbcl-2-Associated X ProteinBCL2 protein, humanBridged Bicyclo Compounds, HeterocyclicMyeloid Cell Leukemia Sequence 1 ProteinProto-Oncogene Proteins c-bcl-2Sulfonamidesvenetoclax

Identifiers

PMID35704690
PMCPMC10653032
OpenAlexW4282926494

What OpenQuestion holds

Textmetadata
LicenceCC BY-NC-ND
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.