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

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Item Type:Article
Title:Deregulation and epigenetic modification of BCL2-family genes cause resistance to venetoclax in hematologic malignancies
Creators Name:Thomalla, D. and Beckmann, L. and Grimm, C. and Oliverio, M. and Meder, L. and Herling, C.D. and Nieper, P. and Feldmann, T. and Merkel, O. and Lorsy, E. and da Palma Guerreiro, A. and von Jan, J. and Kisis, I. and Wasserburger, E. and Claasen, J. and Faitschuk-Meyer, E. and Altmüller, J. and Nürnberg, P. and Yang, T.P. and Lienhard, M. and Herwig, R. and Kreuzer, K.A. and Pallasch, C.P. and Buettner, R. and Schäfer, S.C. and Hartley, J. and Abken, H. and Peifer, M. and Kashkar, H. and Knittel, G. and Eichhorst, B. and Ullrich, R.T. and Herling, M. and Reinhardt, H.C. and Hallek, M. and Schweiger, M.R. and Frenzel, L.P.
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.
Keywords:Apoptosis Regulatory Proteins, B-Cell Chronic Lymphocytic Leukemia, bcl-2-Associated X Protein, Diffuse Large B-Cell Lymphoma, Genetic Epigenesis, Hematologic Neoplasms, Heterocyclic Bridged Bicyclo Compounds, Myeloid Cell Leukemia Sequence 1 Protein, Neoplasm Drug Resistance, Proto-Oncogene Proteins c-bcl-2
Publisher:American Society of Hematology
Page Range:2113-2126
Date:17 November 2022
Additional Information: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.
Official Publication:https://doi.org/10.1182/blood.2021014304
PubMed:View item in PubMed

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