Longitudinal omics data and preclinical treatment suggest the proteasome inhibitor carfilzomib as therapy for ibrutinib-resistant CLL
Abstract Chronic lymphocytic leukemia is a malignant lymphoproliferative disorder for which primary or acquired drug resistance represents a major challenge. To investigate the underlying molecular mechanisms, we generate a mouse model of ibrutinib resistance, in which, after initial treatment respo...
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56318-7 |
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| author | Lavinia Arseni Gianluca Sigismondo Haniyeh Yazdanparast Johanne U. Hermansen Norman Mack Sibylle Ohl Verena Kalter Murat Iskar Mathias Kalxdorf Dennis Friedel Mandy Rettel Yashna Paul Ingo Ringshausen Eric Eldering Julie Dubois Arnon P. Kater Marc Zapatka Philipp M. Roessner Eugen Tausch Stephan Stilgenbauer Sascha Dietrich Mikhail M. Savitski Sigrid S. Skånland Jeroen Krijgsveld Peter Lichter Martina Seiffert |
| author_facet | Lavinia Arseni Gianluca Sigismondo Haniyeh Yazdanparast Johanne U. Hermansen Norman Mack Sibylle Ohl Verena Kalter Murat Iskar Mathias Kalxdorf Dennis Friedel Mandy Rettel Yashna Paul Ingo Ringshausen Eric Eldering Julie Dubois Arnon P. Kater Marc Zapatka Philipp M. Roessner Eugen Tausch Stephan Stilgenbauer Sascha Dietrich Mikhail M. Savitski Sigrid S. Skånland Jeroen Krijgsveld Peter Lichter Martina Seiffert |
| author_sort | Lavinia Arseni |
| collection | DOAJ |
| description | Abstract Chronic lymphocytic leukemia is a malignant lymphoproliferative disorder for which primary or acquired drug resistance represents a major challenge. To investigate the underlying molecular mechanisms, we generate a mouse model of ibrutinib resistance, in which, after initial treatment response, relapse under therapy occurrs with an aggressive outgrowth of malignant cells, resembling observations in patients. A comparative analysis of exome, transcriptome and proteome of sorted leukemic murine cells during treatment and after relapse suggests alterations in the proteasome activity as a driver of ibrutinib resistance. Preclinical treatment with the irreversible proteasome inhibitor carfilzomib administered upon ibrutinib resistance prolongs survival of mice. Longitudinal proteomic analysis of ibrutinib-resistant patients identifies deregulation in protein post-translational modifications. Additionally, cells from ibrutinib-resistant patients effectively respond to several proteasome inhibitors in co-culture assays. Altogether, our results from orthogonal omics approaches identify proteasome inhibition as potentially attractive treatment for chronic lymphocytic leukemia patients resistant or refractory to ibrutinib. |
| format | Article |
| id | doaj-art-9891b66aa9924ab9b1b6560bd4a79c0e |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-9891b66aa9924ab9b1b6560bd4a79c0e2025-01-26T12:41:28ZengNature PortfolioNature Communications2041-17232025-01-0116111610.1038/s41467-025-56318-7Longitudinal omics data and preclinical treatment suggest the proteasome inhibitor carfilzomib as therapy for ibrutinib-resistant CLLLavinia Arseni0Gianluca Sigismondo1Haniyeh Yazdanparast2Johanne U. Hermansen3Norman Mack4Sibylle Ohl5Verena Kalter6Murat Iskar7Mathias Kalxdorf8Dennis Friedel9Mandy Rettel10Yashna Paul11Ingo Ringshausen12Eric Eldering13Julie Dubois14Arnon P. Kater15Marc Zapatka16Philipp M. Roessner17Eugen Tausch18Stephan Stilgenbauer19Sascha Dietrich20Mikhail M. Savitski21Sigrid S. Skånland22Jeroen Krijgsveld23Peter Lichter24Martina Seiffert25Division of Molecular Genetics, German Cancer Research Center (DKFZ)Division of Proteomics of Stem Cells and Cancer, German Cancer Research CenterDivision of Molecular Genetics, German Cancer Research Center (DKFZ)Department of Cancer Immunology, Institute for Cancer Research, Oslo University HospitalDivision of Molecular Genetics, German Cancer Research Center (DKFZ)Division of Molecular Genetics, German Cancer Research Center (DKFZ)Division of Molecular Genetics, German Cancer Research Center (DKFZ)Division of Molecular Genetics, German Cancer Research Center (DKFZ)Cellzome, a GSK CompanyDivision of Neuropathology, German Cancer Research Center (DKFZ)EMBL, Proteomics Core FacilityDivision of Molecular Genetics, German Cancer Research Center (DKFZ)Department of Haematology, Jeffrey Cheah Biomedical Centre, University of CambridgeDepartment of Experimental Immunology, Cancer Center Amsterdam, Amsterdam Institute for Infection and Immunity, Amsterdam University Medical Centers, University of AmsterdamDepartment of Hematology, Cancer Center Amsterdam, Amsterdam Institute for Infection and Immunity, Lymphoma and Myeloma Center Amsterdam, Amsterdam University Medical Centers, University of AmsterdamDepartment of Hematology, Cancer Center Amsterdam, Amsterdam Institute for Infection and Immunity, Lymphoma and Myeloma Center Amsterdam, Amsterdam University Medical Centers, University of AmsterdamDivision of Molecular Genetics, German Cancer Research Center (DKFZ)Division of Molecular Genetics, German Cancer Research Center (DKFZ)Division of CLL, Department of Internal Medicine III, Ulm UniversityDivision of CLL, Department of Internal Medicine III, Ulm UniversityHeidelberg University, Department of HematologyEMBL, Proteomics Core FacilityDepartment of Cancer Immunology, Institute for Cancer Research, Oslo University HospitalDivision of Proteomics of Stem Cells and Cancer, German Cancer Research CenterDivision of Molecular Genetics, German Cancer Research Center (DKFZ)Division of Molecular Genetics, German Cancer Research Center (DKFZ)Abstract Chronic lymphocytic leukemia is a malignant lymphoproliferative disorder for which primary or acquired drug resistance represents a major challenge. To investigate the underlying molecular mechanisms, we generate a mouse model of ibrutinib resistance, in which, after initial treatment response, relapse under therapy occurrs with an aggressive outgrowth of malignant cells, resembling observations in patients. A comparative analysis of exome, transcriptome and proteome of sorted leukemic murine cells during treatment and after relapse suggests alterations in the proteasome activity as a driver of ibrutinib resistance. Preclinical treatment with the irreversible proteasome inhibitor carfilzomib administered upon ibrutinib resistance prolongs survival of mice. Longitudinal proteomic analysis of ibrutinib-resistant patients identifies deregulation in protein post-translational modifications. Additionally, cells from ibrutinib-resistant patients effectively respond to several proteasome inhibitors in co-culture assays. Altogether, our results from orthogonal omics approaches identify proteasome inhibition as potentially attractive treatment for chronic lymphocytic leukemia patients resistant or refractory to ibrutinib.https://doi.org/10.1038/s41467-025-56318-7 |
| spellingShingle | Lavinia Arseni Gianluca Sigismondo Haniyeh Yazdanparast Johanne U. Hermansen Norman Mack Sibylle Ohl Verena Kalter Murat Iskar Mathias Kalxdorf Dennis Friedel Mandy Rettel Yashna Paul Ingo Ringshausen Eric Eldering Julie Dubois Arnon P. Kater Marc Zapatka Philipp M. Roessner Eugen Tausch Stephan Stilgenbauer Sascha Dietrich Mikhail M. Savitski Sigrid S. Skånland Jeroen Krijgsveld Peter Lichter Martina Seiffert Longitudinal omics data and preclinical treatment suggest the proteasome inhibitor carfilzomib as therapy for ibrutinib-resistant CLL Nature Communications |
| title | Longitudinal omics data and preclinical treatment suggest the proteasome inhibitor carfilzomib as therapy for ibrutinib-resistant CLL |
| title_full | Longitudinal omics data and preclinical treatment suggest the proteasome inhibitor carfilzomib as therapy for ibrutinib-resistant CLL |
| title_fullStr | Longitudinal omics data and preclinical treatment suggest the proteasome inhibitor carfilzomib as therapy for ibrutinib-resistant CLL |
| title_full_unstemmed | Longitudinal omics data and preclinical treatment suggest the proteasome inhibitor carfilzomib as therapy for ibrutinib-resistant CLL |
| title_short | Longitudinal omics data and preclinical treatment suggest the proteasome inhibitor carfilzomib as therapy for ibrutinib-resistant CLL |
| title_sort | longitudinal omics data and preclinical treatment suggest the proteasome inhibitor carfilzomib as therapy for ibrutinib resistant cll |
| url | https://doi.org/10.1038/s41467-025-56318-7 |
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