Inhibition of casein kinase 2 sensitizes mantle cell lymphoma to venetoclax through MCL-1 downregulation
BCL-2 family proteins are frequently aberrantly expressed in mantle cell lymphoma (MCL). Recently, the BCL-2-specific inhibitor venetoclax has been approved by the US Food and Drug Administration for chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). In MCL, venetoclax has shown pr...
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| Published in: | Haematologica (Roma) Vol. 108; no. 3; pp. 797 - 810 |
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| Main Authors: | , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
Italy
Fondazione Ferrata Storti
01.03.2023
Ferrata Storti Foundation |
| Subjects: | |
| ISSN: | 0390-6078, 1592-8721, 1592-8721 |
| Online Access: | Get full text |
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| Summary: | BCL-2 family proteins are frequently aberrantly expressed in mantle cell lymphoma (MCL). Recently, the BCL-2-specific inhibitor venetoclax has been approved by the US Food and Drug Administration for chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). In MCL, venetoclax has shown promising efficacy in early clinical trials; however, a significant subset of patients is resistant. By conducting a kinome-centered CRISPR-Cas9 knockout sensitizer screen, we identified casein kinase 2 (CK2) as a major regulator of venetoclax resistance in MCL. Interestingly, CK2 is over-expressed in MCL and high CK2 expression is associated with poor patient survival. Targeting of CK2, either by inducible short hairpin RNA (shRNA)-mediated knockdown of CK2 or by the CK2-inhibitor silmitasertib, did not affect cell viability by itself, but strongly synergized with venetoclax in both MCL cell lines and primary samples, also if combined with ibrutinib. Furthermore, targeting of CK2 reduced MCL-1 levels, which involved impaired MCL-1 translation by inhibition of eIF4F complex assembly, without affecting BCL-2 and BCL-XL expression. Combined, this results in enhanced BCL-2 dependence and, consequently, venetoclax sensitization. In cocultures, targeting of CK2 overcame stroma-mediated venetoclax resistance of MCL cells. Taken together, our findings indicate that targeting of CK2 sensitizes MCL cells to venetoclax through downregulation of MCL-1. These novel insights provide a strong rationale for combining venetoclax with CK2 inhibition as therapeutic strategy for MCL patients. |
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| Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Disclosures Contributions No conflicts of interest to disclose. YJT designed the research, performed experiments, analyzed the data, and wrote the manuscript; MFMdR designed the research and performed bioinformatics; NS performed experiments; RLB and MJK provided materials; JG, EE and STP analyzed the data and revised the manuscript; APK supervised the study, analyzed data and revised the manuscript; MS designed and supervised the study, analyzed data and wrote the manuscript. All authors edited the manuscript. The Perl, R, and Python scripts used for analyzing the CRISPR screen are available in the public GitHub repository (https://github.com/MFMdeRooij/CRISPRscreen). Raw data and the list of genes for which their targeting gRNAs were depleted in the venetoclax-treated arm are provided in Online Supplementary Table S3. Expression profile data analyzed in this study were obtained from Gene Expression Omnibus (GEO) at GSE93291, GSE132929, and GSE28491 and from the EMBL European Bioinformatics Institute database at E-MTAB-1771. Data-sharing statement |
| ISSN: | 0390-6078 1592-8721 1592-8721 |
| DOI: | 10.3324/haematol.2022.281668 |