Deregulation and epigenetic modification of BCL2-family genes cause resistance to venetoclax in hematologic malignancies
Thomalla D, Beckmann L, Grimm C, Oliverio M, Meder L, Herling CD, Nieper P, Feldmann T, Merkel O, Lorsy E, Guerreiro ADP, Von Jan J, Kisis I, Wasserburger E, Claasen J, Faitschuk-Meyer E, Altmueller J, Nuernberg P, Yang TP, Lienhard M, Herwig R, Kreuzer KA, Pallasch CP, Buettner R, Schaefer SC, Hartley J, Abken H, Peifer M, Kashkar H, Knittel G, Eichhorst B, Ullrich RT, Herling M, Reinhardt HC, Hallek M, Schweiger MR, Frenzel LP (2022)
Publication Type: Journal article
Publication year: 2022
Journal
Book Volume: 140
Pages Range: 2113-2126
Journal Issue: 20
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.
Authors with CRIS profile
Involved external institutions
Universität zu Köln
Germany (DE)
Universitätsklinikum Regensburg
Germany (DE)
Universität Duisburg-Essen (UDE)
Germany (DE)
Miltenyi Biotec GmbH
Germany (DE)
Max-Planck-Institut für molekulare Genetik / Max Planck Institute for Molecular Genetics
Germany (DE)
Germany (DE)
Universitätsklinikum Regensburg
Germany (DE)
Universität Duisburg-Essen (UDE)
Germany (DE)
Miltenyi Biotec GmbH
Germany (DE)
Max-Planck-Institut für molekulare Genetik / Max Planck Institute for Molecular Genetics
Germany (DE)
How to cite
APA:
Thomalla, D., Beckmann, L., Grimm, C., Oliverio, M., Meder, L., Herling, C.D.,... Frenzel, L.P. (2022). Deregulation and epigenetic modification of BCL2-family genes cause resistance to venetoclax in hematologic malignancies. Blood, 140(20), 2113-2126. https://dx.doi.org/10.1182/blood.2021014304
MLA:
Thomalla, D., et al. "Deregulation and epigenetic modification of BCL2-family genes cause resistance to venetoclax in hematologic malignancies." Blood 140.20 (2022): 2113-2126.
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