A sumoylation program is essential for maintaining the mitotic fidelity in proliferating mantle cell lymphoma cells
Abstract Background Mantle cell lymphoma (MCL) is a rare, highly heterogeneous type of B-cell non-Hodgkin’s lymphoma. The sumoylation pathway is known to be upregulated in many cancers including lymphoid malignancies. However, little is known about its oncogenic role in MCL. Methods Levels of sumoyl...
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| Format: | Article |
| Language: | English |
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BMC
2022-07-01
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| Series: | Experimental Hematology & Oncology |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s40164-022-00293-y |
| _version_ | 1828541626893467648 |
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| author | Walter Hanel Pushpa Lata Youssef Youssef Ha Tran Liudmyla Tsyba Lalit Sehgal Bradley W. Blaser Dennis Huszar JoBeth Helmig-Mason Liwen Zhang Morgan S. Schrock Matthew K. Summers Wing Keung Chan Alexander Prouty Bethany L. Mundy-Bosse Selina Chen-Kiang Alexey V. Danilov Kami Maddocks Robert A. Baiocchi Lapo Alinari |
| author_facet | Walter Hanel Pushpa Lata Youssef Youssef Ha Tran Liudmyla Tsyba Lalit Sehgal Bradley W. Blaser Dennis Huszar JoBeth Helmig-Mason Liwen Zhang Morgan S. Schrock Matthew K. Summers Wing Keung Chan Alexander Prouty Bethany L. Mundy-Bosse Selina Chen-Kiang Alexey V. Danilov Kami Maddocks Robert A. Baiocchi Lapo Alinari |
| author_sort | Walter Hanel |
| collection | DOAJ |
| description | Abstract Background Mantle cell lymphoma (MCL) is a rare, highly heterogeneous type of B-cell non-Hodgkin’s lymphoma. The sumoylation pathway is known to be upregulated in many cancers including lymphoid malignancies. However, little is known about its oncogenic role in MCL. Methods Levels of sumoylation enzymes and sumoylated proteins were quantified in MCL cell lines and primary MCL patient samples by scRNA sequencing and immunoblotting. The sumoylation enzyme SAE2 was genetically and pharmacologically targeted with shRNA and TAK-981 (subasumstat). The effects of SAE2 inhibition on MCL proliferation and cell cycle were evaluated using confocal microscopy, live-cell microscopy, and flow cytometry. Immunoprecipitation and orbitrap mass spectrometry were used to identify proteins targeted by sumoylation in MCL cells. Results MCL cells have significant upregulation of the sumoylation pathway at the level of the enzymes SAE1 and SAE2 which correlated with poor prognosis and induction of mitosis associated genes. Selective inhibition of SAE2 with TAK-981 results in significant MCL cell death in vitro and in vivo with mitotic dysregulation being an important mechanism of action. We uncovered a sumoylation program in mitotic MCL cells comprised of multiple pathways which could be directly targeted with TAK-981. Centromeric localization of topoisomerase 2A, a gene highly upregulated in SAE1 and SAE2 overexpressing MCL cells, was lost with TAK-981 treatment likely contributing to the mitotic dysregulation seen in MCL cells. Conclusions This study not only validates SAE2 as a therapeutic target in MCL but also opens the door to further mechanistic work to uncover how to best use desumoylation therapy to treat MCL and other lymphoid malignancies. |
| first_indexed | 2024-12-12T01:42:35Z |
| format | Article |
| id | doaj.art-cf2c01ff3b1143099fc83be472ac2f3f |
| institution | Directory Open Access Journal |
| issn | 2162-3619 |
| language | English |
| last_indexed | 2024-12-12T01:42:35Z |
| publishDate | 2022-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Experimental Hematology & Oncology |
| spelling | doaj.art-cf2c01ff3b1143099fc83be472ac2f3f2022-12-22T00:42:39ZengBMCExperimental Hematology & Oncology2162-36192022-07-0111111910.1186/s40164-022-00293-yA sumoylation program is essential for maintaining the mitotic fidelity in proliferating mantle cell lymphoma cellsWalter Hanel0Pushpa Lata1Youssef Youssef2Ha Tran3Liudmyla Tsyba4Lalit Sehgal5Bradley W. Blaser6Dennis Huszar7JoBeth Helmig-Mason8Liwen Zhang9Morgan S. Schrock10Matthew K. Summers11Wing Keung Chan12Alexander Prouty13Bethany L. Mundy-Bosse14Selina Chen-Kiang15Alexey V. Danilov16Kami Maddocks17Robert A. Baiocchi18Lapo Alinari19Division of Hematology, Department of Medicine, The James Cancer Hospital and Solove Research Institute, The Ohio State UniversityDivision of Hematology, Department of Medicine, The James Cancer Hospital and Solove Research Institute, The Ohio State UniversityDivision of Hematology, Department of Medicine, The James Cancer Hospital and Solove Research Institute, The Ohio State UniversityDivision of Hematology, Department of Medicine, The James Cancer Hospital and Solove Research Institute, The Ohio State UniversityDivision of Hematology, Department of Medicine, The James Cancer Hospital and Solove Research Institute, The Ohio State UniversityDivision of Hematology, Department of Medicine, The James Cancer Hospital and Solove Research Institute, The Ohio State UniversityDivision of Hematology, Department of Medicine, The James Cancer Hospital and Solove Research Institute, The Ohio State UniversityJounce TherapeuticsDivision of Hematology, Department of Medicine, The James Cancer Hospital and Solove Research Institute, The Ohio State UniversityProteomics and Mass Spectrometry Facility, The Ohio State UniversityDepartment of Radiation Oncology, The James Cancer Hospital and Solove Research Institute, The Ohio State UniversityDepartment of Radiation Oncology, The James Cancer Hospital and Solove Research Institute, The Ohio State UniversityDivision of Hematology, Department of Medicine, The James Cancer Hospital and Solove Research Institute, The Ohio State UniversityDivision of Hematology, Department of Medicine, The James Cancer Hospital and Solove Research Institute, The Ohio State UniversityDivision of Hematology, Department of Medicine, The James Cancer Hospital and Solove Research Institute, The Ohio State UniversityWeil Cornell Medical CollegeCity of Hope National Medical CenterDivision of Hematology, Department of Medicine, The James Cancer Hospital and Solove Research Institute, The Ohio State UniversityDivision of Hematology, Department of Medicine, The James Cancer Hospital and Solove Research Institute, The Ohio State UniversityDivision of Hematology, Department of Medicine, The James Cancer Hospital and Solove Research Institute, The Ohio State UniversityAbstract Background Mantle cell lymphoma (MCL) is a rare, highly heterogeneous type of B-cell non-Hodgkin’s lymphoma. The sumoylation pathway is known to be upregulated in many cancers including lymphoid malignancies. However, little is known about its oncogenic role in MCL. Methods Levels of sumoylation enzymes and sumoylated proteins were quantified in MCL cell lines and primary MCL patient samples by scRNA sequencing and immunoblotting. The sumoylation enzyme SAE2 was genetically and pharmacologically targeted with shRNA and TAK-981 (subasumstat). The effects of SAE2 inhibition on MCL proliferation and cell cycle were evaluated using confocal microscopy, live-cell microscopy, and flow cytometry. Immunoprecipitation and orbitrap mass spectrometry were used to identify proteins targeted by sumoylation in MCL cells. Results MCL cells have significant upregulation of the sumoylation pathway at the level of the enzymes SAE1 and SAE2 which correlated with poor prognosis and induction of mitosis associated genes. Selective inhibition of SAE2 with TAK-981 results in significant MCL cell death in vitro and in vivo with mitotic dysregulation being an important mechanism of action. We uncovered a sumoylation program in mitotic MCL cells comprised of multiple pathways which could be directly targeted with TAK-981. Centromeric localization of topoisomerase 2A, a gene highly upregulated in SAE1 and SAE2 overexpressing MCL cells, was lost with TAK-981 treatment likely contributing to the mitotic dysregulation seen in MCL cells. Conclusions This study not only validates SAE2 as a therapeutic target in MCL but also opens the door to further mechanistic work to uncover how to best use desumoylation therapy to treat MCL and other lymphoid malignancies.https://doi.org/10.1186/s40164-022-00293-yUBA2SAE1SAE2UBC9UBE2ITopoisomerase |
| spellingShingle | Walter Hanel Pushpa Lata Youssef Youssef Ha Tran Liudmyla Tsyba Lalit Sehgal Bradley W. Blaser Dennis Huszar JoBeth Helmig-Mason Liwen Zhang Morgan S. Schrock Matthew K. Summers Wing Keung Chan Alexander Prouty Bethany L. Mundy-Bosse Selina Chen-Kiang Alexey V. Danilov Kami Maddocks Robert A. Baiocchi Lapo Alinari A sumoylation program is essential for maintaining the mitotic fidelity in proliferating mantle cell lymphoma cells Experimental Hematology & Oncology UBA2 SAE1 SAE2 UBC9 UBE2I Topoisomerase |
| title | A sumoylation program is essential for maintaining the mitotic fidelity in proliferating mantle cell lymphoma cells |
| title_full | A sumoylation program is essential for maintaining the mitotic fidelity in proliferating mantle cell lymphoma cells |
| title_fullStr | A sumoylation program is essential for maintaining the mitotic fidelity in proliferating mantle cell lymphoma cells |
| title_full_unstemmed | A sumoylation program is essential for maintaining the mitotic fidelity in proliferating mantle cell lymphoma cells |
| title_short | A sumoylation program is essential for maintaining the mitotic fidelity in proliferating mantle cell lymphoma cells |
| title_sort | sumoylation program is essential for maintaining the mitotic fidelity in proliferating mantle cell lymphoma cells |
| topic | UBA2 SAE1 SAE2 UBC9 UBE2I Topoisomerase |
| url | https://doi.org/10.1186/s40164-022-00293-y |
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