Thomalla, D., Beckmann, L., Grimm, C., Oliverio, M., Meder, L., Herling, C. D., Nieper, P., Feldmann, T., Merkel, O., Lorsy, E., Guerreiro, A. da Palma, von Jan, J., Kisis, I., Wasserburger, E., Claasen, J., Faitschuk-Meyer, E., Altmueller, J., Nuernberg, P., Yang, T. -P., Lienhard, M., Herwig, R., Kreuzer, K. -A., Pallasch, C. P., Buettner, R., Schaefer, 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. (2022). Deregulation and epigenetic modification of BCL2-family genes cause resistance to venetoclax in hematologic malignancies. Blood, 140 (20). S. 2113 - 2127. WASHINGTON: AMER SOC HEMATOLOGY. ISSN 1528-0020

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Thomalla, D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Beckmann, L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Grimm, C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Oliverio, M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Meder, L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Herling, C. D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nieper, P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Feldmann, T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Merkel, O.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lorsy, E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Guerreiro, A. da PalmaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
von Jan, J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kisis, I.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wasserburger, E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Claasen, J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Faitschuk-Meyer, E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Altmueller, J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuernberg, P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yang, T. -P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lienhard, M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Herwig, R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kreuzer, K. -A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pallasch, C. P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buettner, R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schaefer, S. C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hartley, J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Abken, H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peifer, M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kashkar, H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Knittel, G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Eichhorst, B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ullrich, R. T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Herling, M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reinhardt, H. C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hallek, M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schweiger, M. R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Frenzel, L. P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-686249
DOI: 10.1182/blood.2021014304
Journal or Publication Title: Blood
Volume: 140
Number: 20
Page Range: S. 2113 - 2127
Date: 2022
Publisher: AMER SOC HEMATOLOGY
Place of Publication: WASHINGTON
ISSN: 1528-0020
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
PROGNOSTIC-SIGNIFICANCE; DNA METHYLATION; CELL-DEATH; EXPRESSION; BCL-2; APOPTOSIS; PUMA; BAX; LEUKEMIA; CANCERMultiple languages
HematologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/68624

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