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  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, C. D., et al. (2022). Deregulation and epigenetic modification of BCL2-family genes cause resistance to venetoclax in hematologic malignancies. Blood, 2022. doi:10.1182/blood.2021014304.

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 Creators:
Thomalla, Daniel , Author
Beckmann, Laura , Author
Grimm , Christina, Author
Oliverio, Matteo , Author
Meder, Lydia , Author
Herling, Carmen Diana , Author
Nieper, Pascal , Author
Feldmann, Thorsten , Author
Merkel, Olaf, Author
Lorsy, Eva, Author
da Palma Guerreiro , Alexandra , Author
von Jan, Jana , Author
Kisis, Ilmars , Author
Wasserburger, Elena , Author
Claasen, Julia, Author
Faitschuk-Meyer, Elena , Author
Altmüller, Janine, Author
Nürnberg, Peter, Author
Yang, Tsun-Po , Author
Lienhard, Matthias1, Author           
Herwig, Ralf1, Author           Kreuzer, Karl-Anton , AuthorPallasch, Christian P. , AuthorBuettner, Reinhard , AuthorSchäfer, Stephan Christian, AuthorHartley, Jordan , AuthorAbken, Hinrich , AuthorPeifer, Martin, AuthorKashkar, Hamid , AuthorKnittel, Gero, AuthorEichhorst , Barbara , AuthorUllrich, Roland T. , AuthorHerling, Marco , AuthorReinhardt, Hans Christian , AuthorHallek, Michael , AuthorSchweiger, Michal R. , AuthorFrenzel, Lukas P. , Author more..
Affiliations:
1Bioinformatics (Ralf Herwig), Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2385701              

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Free keywords: Lymphoid Neoplasia
 Abstract: The BCL2 inhibitor venetoclax has been approved to treat different hematological malignancies. Since there is no common genetic alteration causing resistance to venetoclax in 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 CRISPR/Cas9 screening to investigate venetoclax resistance in aggressive lymphoma and high-risk CLL patients. We identified a regulatory CpG island within the PUMA promoter which is methylated upon venetoclax treatment, mediating PUMA downregulation on transcript and protein level. PUMA expression and sensitivity towards venetoclax can be restored by inhibition of methyltransferases. We can demonstrate that loss of PUMA results in metabolic reprogramming with higher OXPHOS and ATP production, resembling the metabolic phenotype that is seen upon venetoclax resistance. While 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 towards 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 DLBCL 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.

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Language(s): eng - English
 Dates: 2022-06-012022-06-15
 Publication Status: Published online
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: DOI: 10.1182/blood.2021014304
 Degree: -

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Title: Blood
  Other : Blood
Source Genre: Journal
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Publ. Info: Philadelphia, Pa. : W.B. Saunders
Pages: - Volume / Issue: 2022 Sequence Number: - Start / End Page: - Identifier: ISSN: 0006-4971 (print) 1528-0020 (online)
PMID: 35704690
CoNE: https://pure.mpg.de/cone/journals/resource/954925385125