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

Humans Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy Myeloid Cell Leukemia Sequence 1 Protein / genetics Proto-Oncogene Proteins c-bcl-2 / genetics bcl-2-Associated X Protein / metabolism Drug Resistance, Neoplasm / genetics Apoptosis Regulatory Proteins / genetics Bridged Bicyclo Compounds, Heterocyclic / pharmacology Lymphoma, Large B-Cell, Diffuse / pathology Hematologic Neoplasms / drug therapy Epigenesis, Genetic

Journal

Blood
ISSN: 1528-0020
Titre abrégé: Blood
Pays: United States
ID NLM: 7603509

Informations de publication

Date de publication:
17 11 2022
Historique:
accepted: 01 06 2022
received: 04 10 2021
pubmed: 16 6 2022
medline: 22 11 2022
entrez: 15 6 2022
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1182/blood.2021014304 PMID: 35704690 PMC: PMC10653032
pubmed: 35704690
pii: S0006-4971(22)00773-X
doi: 10.1182/blood.2021014304
pmc: PMC10653032
doi:

Substances chimiques

venetoclax N54AIC43PW
Myeloid Cell Leukemia Sequence 1 Protein 0
Proto-Oncogene Proteins c-bcl-2 0
bcl-2-Associated X Protein 0
Apoptosis Regulatory Proteins 0
Bridged Bicyclo Compounds, Heterocyclic 0
BCL2 protein, human 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

2113-2126

Commentaires et corrections

Type : CommentIn

Informations de copyright

© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.

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Auteurs

D Thomalla (D)

Faculty of Medicine and Cologne University Hospital, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany.
Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.

L Beckmann (L)

Faculty of Medicine and Cologne University Hospital, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany.
Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
ORCID: 0000-0001-5207-8991

C Grimm (C)

Institute for Translational Epigenetics, Medical Faculty, University of Cologne, Cologne, Germany.
Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.
ORCID: 0000-0002-4676-8870

M Oliverio (M)

Faculty of Medicine and Cologne University Hospital, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany.
Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
ORCID: 0000-0002-7969-2796

L Meder (L)

Faculty of Medicine and Cologne University Hospital, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany.
Mildred Scheel School of Oncology Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.

C D Herling (CD)

Faculty of Medicine and Cologne University Hospital, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany.
Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
Clinic of Hematology, Cellular Therapy and Hemostaseology, University of Leipzig, Leipzig, Germany.

P Nieper (P)

Faculty 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 Feldmann (T)

Institute for Translational Epigenetics, Medical Faculty, University of Cologne, Cologne, Germany.

O Merkel (O)

Faculty of Medicine and Cologne University Hospital, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany.
Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.

E Lorsy (E)

Faculty of Medicine and Cologne University Hospital, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany.
Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.

A da Palma Guerreiro (A)

Faculty of Medicine and Cologne University Hospital, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany.
Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.

J von Jan (J)

Faculty 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 Kisis (I)

Faculty 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 Wasserburger (E)

Institute for Translational Epigenetics, Medical Faculty, University of Cologne, Cologne, Germany.

J Claasen (J)

Faculty of Medicine and Cologne University Hospital, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany.
Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.

E Faitschuk-Meyer (E)

Miltenyi Biotec B.V. & Co. KG, Bergisch-Gladbach, Germany.

J Altmüller (J)

Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.
ORCID: 0000-0003-4372-1521

P Nürnberg (P)

Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.
Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
ORCID: 0000-0002-7228-428X

T-P Yang (TP)

Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
Center of Integrated Oncology Cologne-Bonn, Medical Faculty, Department of Translational Genomics, University of Cologne, Cologne, Germany.

M Lienhard (M)

Department of Computational Molecular Biology, Max-Planck-Institute for Molecular Genetics, Berlin, Germany.
ORCID: 0000-0002-2549-3142

R Herwig (R)

Department of Computational Molecular Biology, Max-Planck-Institute for Molecular Genetics, Berlin, Germany.
ORCID: 0000-0002-9335-1760

K-A Kreuzer (KA)

Faculty of Medicine and Cologne University Hospital, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany.
Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.

C P Pallasch (CP)

Faculty of Medicine and Cologne University Hospital, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany.
Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.

R Büttner (R)

Department of Pathology, University of Cologne, Cologne, Germany.

S C Schäfer (SC)

Department of Pathology, University of Cologne, Cologne, Germany.
Institut für Pathologie im Medizin Campus Bodensee, Friedrichshafen, Germany.
ORCID: 0000-0002-2116-1212

J Hartley (J)

RCI, Regensburg Center for Interventional Immunology, University Hospital of Regensburg, Regensburg, Germany.

H Abken (H)

RCI, Regensburg Center for Interventional Immunology, University Hospital of Regensburg, Regensburg, Germany.
ORCID: 0000-0002-4302-3240

M Peifer (M)

Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
Center of Integrated Oncology Cologne-Bonn, Medical Faculty, Department of Translational Genomics, University of Cologne, Cologne, Germany.
ORCID: 0000-0002-5243-5503

H Kashkar (H)

Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
Institute for Molecular Immunologie, University of Cologne, Cologne, Germany.

G Knittel (G)

Department 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 Eichhorst (B)

Faculty 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 Ullrich (RT)

Faculty of Medicine and Cologne University Hospital, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany.
Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.

M Herling (M)

Faculty of Medicine and Cologne University Hospital, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany.
Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
Clinic of Hematology, Cellular Therapy and Hemostaseology, University of Leipzig, Leipzig, Germany.

H C Reinhardt (HC)

Department of Hematology and Stem Cell Transplantation, University Hospital Essen, University Duisburg-Essen, German Cancer Consortium (DKTK Partner Site Essen), Essen, Germany.

M Hallek (M)

Faculty of Medicine and Cologne University Hospital, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany.
Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.

M R Schweiger (MR)

Institute for Translational Epigenetics, Medical Faculty, University of Cologne, Cologne, Germany.
Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.
Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.

L P Frenzel (LP)

Faculty of Medicine and Cologne University Hospital, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany.
Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Deregulation and epigenetic modification of...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Caractéristiques de la maladie › Maladie chronique › Leucémie chronique lymphocytaire à cellules B › Deregulation and epigenetic modification of...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines tumorales › Protéines oncogènes › Protéines proto-oncogènes › Protéines proto-oncogènes c-bcl-2 › Protéine Mcl-1 › Deregulation and epigenetic modification of...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines tumorales › Protéines oncogènes › Protéines proto-oncogènes › Protéines proto-oncogènes c-bcl-2 › Deregulation and epigenetic modification of...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protéines régulatrices de l'apoptose › Protéine Bax › Deregulation and epigenetic modification of...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes pharmacologiques › Résistance aux substances › Résistance aux médicaments antinéoplasiques › Deregulation and epigenetic modification of...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protéines régulatrices de l'apoptose › Deregulation and epigenetic modification of...
questionsmedicales.fr › Composés hétérocycliques › Composés hétérocycliques, cycle ponté › Composés hétérocycliques bicycliques › Deregulation and epigenetic modification of...
questionsmedicales.fr › Maladies du système immunitaire › Syndromes immunoprolifératifs › Syndromes lymphoprolifératifs › Lymphomes › Lymphome malin non hodgkinien › Lymphome B › Lymphome B diffus à grandes cellules › Deregulation and epigenetic modification of...
questionsmedicales.fr › Hémopathies et maladies lymphatiques › Hémopathies › Tumeurs hématologiques › Deregulation and epigenetic modification of...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Épigenèse génétique › Deregulation and epigenetic modification of...