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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Vydané v:	Haematologica (Roma) Ročník 108; číslo 3; s. 797 - 810
Hlavní autori:	Thus, Yvonne J., De Rooij, Martin F.M., Swier, Nathalie, Beijersbergen, Roderick L., Guikema, Jeroen E.J., Kersten, Marie-José, Eldering, Eric, Pals, Steven T., Kater, Arnon P., Spaargaren, Marcel
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	Italy Fondazione Ferrata Storti 01.03.2023 Ferrata Storti Foundation
Predmet:	Adult Antineoplastic Agents - pharmacology Antineoplastic Agents - therapeutic use Bridged Bicyclo Compounds, Heterocyclic - pharmacology Bridged Bicyclo Compounds, Heterocyclic - therapeutic use Casein Kinase II - genetics Casein Kinase II - metabolism Cell Line, Tumor Down-Regulation Humans Lymphoma, Mantle-Cell - drug therapy Lymphoma, Mantle-Cell - genetics Lymphoma, Mantle-Cell - metabolism Myeloid Cell Leukemia Sequence 1 Protein - metabolism Non-Hodgkin Lymphoma Proto-Oncogene Proteins c-bcl-2
ISSN:	0390-6078, 1592-8721, 1592-8721
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Abstract	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.
AbstractList	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. 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.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.
Author	Swier, Nathalie Beijersbergen, Roderick L. Kater, Arnon P. Thus, Yvonne J. Pals, Steven T. Kersten, Marie-José Spaargaren, Marcel Eldering, Eric De Rooij, Martin F.M. Guikema, Jeroen E.J.
AuthorAffiliation	2 Lymphoma and Myeloma Center Amsterdam (LYMMCARE) 3 Cancer Center Amsterdam (CCA), Cancer Biology and Immunology – Target & Therapy Discovery 6 Department of Hematology, Amsterdam UMC, University of Amsterdam 5 The NKI Robotics and Screening Center, The Netherlands Cancer Institute 1 Department of Pathology, Amsterdam UMC, University of Amsterdam 4 Division of Molecular Carcinogenesis, Oncode Institute , The Netherlands Cancer Institute 7 Department of Experimental Immunology, Amsterdam UMC, University of Amsterdam , Amsterdam, The Netherlands
AuthorAffiliation_xml	– name: 5 The NKI Robotics and Screening Center, The Netherlands Cancer Institute – name: 6 Department of Hematology, Amsterdam UMC, University of Amsterdam – name: 4 Division of Molecular Carcinogenesis, Oncode Institute , The Netherlands Cancer Institute – name: 7 Department of Experimental Immunology, Amsterdam UMC, University of Amsterdam , Amsterdam, The Netherlands – name: 1 Department of Pathology, Amsterdam UMC, University of Amsterdam – name: 2 Lymphoma and Myeloma Center Amsterdam (LYMMCARE) – name: 3 Cancer Center Amsterdam (CCA), Cancer Biology and Immunology – Target & Therapy Discovery
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Notes	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
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SubjectTerms	Adult Antineoplastic Agents - pharmacology Antineoplastic Agents - therapeutic use Bridged Bicyclo Compounds, Heterocyclic - pharmacology Bridged Bicyclo Compounds, Heterocyclic - therapeutic use Casein Kinase II - genetics Casein Kinase II - metabolism Cell Line, Tumor Down-Regulation Humans Lymphoma, Mantle-Cell - drug therapy Lymphoma, Mantle-Cell - genetics Lymphoma, Mantle-Cell - metabolism Myeloid Cell Leukemia Sequence 1 Protein - metabolism Non-Hodgkin Lymphoma Proto-Oncogene Proteins c-bcl-2
Title	Inhibition of casein kinase 2 sensitizes mantle cell lymphoma to venetoclax through MCL-1 downregulation
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