![[feed]](/style/images/feed-icon-14x14.png){kind=icon}
Tools
Tools
Preview |
PDF (Original Article)
- Requires a PDF viewer such as GSview, Xpdf or Adobe Acrobat Reader
2MB |
Preview |
PDF (Supplementary Material & Methods)
- Requires a PDF viewer such as GSview, Xpdf or Adobe Acrobat Reader
3MB |
| Item Type: | Article |
|---|---|
| Title: | Deregulation and epigenetic modification of BCL2-family genes cause resistance to venetoclax in hematologic malignancies |
| Creators Name: | Thomalla, D., Beckmann, L., Grimm, C., Oliverio, M., Meder, L., Herling, C.D., Nieper, P., Feldmann, T., Merkel, O., Lorsy, E., da Palma Guerreiro, A., von Jan, J., Kisis, I., Wasserburger, E., Claasen, J., Faitschuk-Meyer, E., Altmüller, J., Nürnberg, P., Yang, T.P., Lienhard, M., Herwig, R., Kreuzer, K.A., Pallasch, C.P., Buettner, R., Schäfer, S.C., Hartley, J., Abken, H., Peifer, M., Kashkar, H., Knittel, G., Eichhorst, B., Ullrich, R.T., Herling, M., Reinhardt, H.C., Hallek, M., 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 |
| Source: | Blood |
| ISSN: | 0006-4971 |
| Publisher: | American Society of Hematology |
| Volume: | 140 |
| Number: | 20 |
| 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 |
Repository Staff Only: item control page
