@article{Thomalla2022, abstract = {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.}, author = {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 Büttner, 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.}, doi = {10.1182/blood.2021014304}, journal = {Blood}, month = {nov}, pages = {2113-2126}, title = {Deregulation and epigenetic modification of BCL2-family genes cause resistance to venetoclax in hematologic malignancies}, url = {https://oadoi.org/10.1182/blood.2021014304}, volume = {140}, year = {2022} }