Targeting DNA2 overcomes metabolic reprogramming in multiple myeloma
Abstract DNA damage resistance is a major barrier to effective DNA-damaging therapy in multiple myeloma (MM). To discover mechanisms through which MM cells overcome DNA damage, we investigate how MM cells become resistant to antisense oligonucleotide (ASO) therapy targeting Interleukin enhancer bind...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-45350-8 |
| _version_ | 1797273930215456768 |
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| author | Natthakan Thongon Feiyang Ma Natalia Baran Pamela Lockyer Jintan Liu Christopher Jackson Ashley Rose Ken Furudate Bethany Wildeman Matteo Marchesini Valentina Marchica Paola Storti Giannalisa Todaro Irene Ganan-Gomez Vera Adema Juan Jose Rodriguez-Sevilla Yun Qing Min Jin Ha Rodrigo Fonseca Caleb Stein Caleb Class Lin Tan Sergio Attanasio Guillermo Garcia-Manero Nicola Giuliani David Berrios Nolasco Andrea Santoni Claudio Cerchione Carlos Bueso-Ramos Marina Konopleva Philip Lorenzi Koichi Takahashi Elisabet Manasanch Gabriella Sammarelli Rashmi Kanagal-Shamanna Andrea Viale Marta Chesi Simona Colla |
| author_facet | Natthakan Thongon Feiyang Ma Natalia Baran Pamela Lockyer Jintan Liu Christopher Jackson Ashley Rose Ken Furudate Bethany Wildeman Matteo Marchesini Valentina Marchica Paola Storti Giannalisa Todaro Irene Ganan-Gomez Vera Adema Juan Jose Rodriguez-Sevilla Yun Qing Min Jin Ha Rodrigo Fonseca Caleb Stein Caleb Class Lin Tan Sergio Attanasio Guillermo Garcia-Manero Nicola Giuliani David Berrios Nolasco Andrea Santoni Claudio Cerchione Carlos Bueso-Ramos Marina Konopleva Philip Lorenzi Koichi Takahashi Elisabet Manasanch Gabriella Sammarelli Rashmi Kanagal-Shamanna Andrea Viale Marta Chesi Simona Colla |
| author_sort | Natthakan Thongon |
| collection | DOAJ |
| description | Abstract DNA damage resistance is a major barrier to effective DNA-damaging therapy in multiple myeloma (MM). To discover mechanisms through which MM cells overcome DNA damage, we investigate how MM cells become resistant to antisense oligonucleotide (ASO) therapy targeting Interleukin enhancer binding factor 2 (ILF2), a DNA damage regulator that is overexpressed in 70% of MM patients whose disease has progressed after standard therapies have failed. Here, we show that MM cells undergo adaptive metabolic rewiring to restore energy balance and promote survival in response to DNA damage activation. Using a CRISPR/Cas9 screening strategy, we identify the mitochondrial DNA repair protein DNA2, whose loss of function suppresses MM cells’ ability to overcome ILF2 ASO−induced DNA damage, as being essential to counteracting oxidative DNA damage. Our study reveals a mechanism of vulnerability of MM cells that have an increased demand for mitochondrial metabolism upon DNA damage activation. |
| first_indexed | 2024-03-07T14:51:10Z |
| format | Article |
| id | doaj.art-0ff32e3e332a47feb2ca0404a6595cec |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-07T14:51:10Z |
| publishDate | 2024-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-0ff32e3e332a47feb2ca0404a6595cec2024-03-05T19:40:12ZengNature PortfolioNature Communications2041-17232024-02-0115111310.1038/s41467-024-45350-8Targeting DNA2 overcomes metabolic reprogramming in multiple myelomaNatthakan Thongon0Feiyang Ma1Natalia Baran2Pamela Lockyer3Jintan Liu4Christopher Jackson5Ashley Rose6Ken Furudate7Bethany Wildeman8Matteo Marchesini9Valentina Marchica10Paola Storti11Giannalisa Todaro12Irene Ganan-Gomez13Vera Adema14Juan Jose Rodriguez-Sevilla15Yun Qing16Min Jin Ha17Rodrigo Fonseca18Caleb Stein19Caleb Class20Lin Tan21Sergio Attanasio22Guillermo Garcia-Manero23Nicola Giuliani24David Berrios Nolasco25Andrea Santoni26Claudio Cerchione27Carlos Bueso-Ramos28Marina Konopleva29Philip Lorenzi30Koichi Takahashi31Elisabet Manasanch32Gabriella Sammarelli33Rashmi Kanagal-Shamanna34Andrea Viale35Marta Chesi36Simona Colla37Department of Leukemia, The University of Texas MD Anderson Cancer CenterDivision of Rheumatology, Department of Internal Medicine, Michigan Medicine, University of MichiganDepartment of Leukemia, The University of Texas MD Anderson Cancer CenterDepartment of Leukemia, The University of Texas MD Anderson Cancer CenterDepartment of Genomic Medicine, The University of Texas MD Anderson Cancer CenterDepartment of Leukemia, The University of Texas MD Anderson Cancer CenterDepartment of Leukemia, The University of Texas MD Anderson Cancer CenterDepartment of Leukemia, The University of Texas MD Anderson Cancer CenterDepartment of Leukemia, The University of Texas MD Anderson Cancer CenterIRCCS Instituto Romagnolo per lo Studio dei Tumori (IRST) Dino AmadoriDepartment of Medicine and Surgery, University of ParmaDepartment of Medicine and Surgery, University of ParmaDepartment of Medicine and Surgery, University of ParmaDepartment of Leukemia, The University of Texas MD Anderson Cancer CenterDepartment of Leukemia, The University of Texas MD Anderson Cancer CenterDepartment of Leukemia, The University of Texas MD Anderson Cancer CenterDepartment of Biostatistics, The University of Texas MD Anderson Cancer CenterDepartment of Biostatistics, The University of Texas MD Anderson Cancer CenterDepartment of Medicine, Mayo ClinicDepartment of Medicine, Mayo ClinicDepartment of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Butler UniversityMetabolomics Core Facility, Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer CenterDepartment of Genomic Medicine, The University of Texas MD Anderson Cancer CenterDepartment of Leukemia, The University of Texas MD Anderson Cancer CenterDepartment of Medicine and Surgery, University of ParmaDepartment of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer CenterDepartment of Leukemia, The University of Texas MD Anderson Cancer CenterIRCCS Instituto Romagnolo per lo Studio dei Tumori (IRST) Dino AmadoriDepartment of Hemopathology, The University of Texas MD Anderson Cancer CenterDepartment of Leukemia, The University of Texas MD Anderson Cancer CenterMetabolomics Core Facility, Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer CenterDepartment of Leukemia, The University of Texas MD Anderson Cancer CenterDepartment of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer CenterDepartment of Medicine and Surgery, University of ParmaDepartment of Hemopathology, The University of Texas MD Anderson Cancer CenterDepartment of Genomic Medicine, The University of Texas MD Anderson Cancer CenterDepartment of Medicine, Mayo ClinicDepartment of Leukemia, The University of Texas MD Anderson Cancer CenterAbstract DNA damage resistance is a major barrier to effective DNA-damaging therapy in multiple myeloma (MM). To discover mechanisms through which MM cells overcome DNA damage, we investigate how MM cells become resistant to antisense oligonucleotide (ASO) therapy targeting Interleukin enhancer binding factor 2 (ILF2), a DNA damage regulator that is overexpressed in 70% of MM patients whose disease has progressed after standard therapies have failed. Here, we show that MM cells undergo adaptive metabolic rewiring to restore energy balance and promote survival in response to DNA damage activation. Using a CRISPR/Cas9 screening strategy, we identify the mitochondrial DNA repair protein DNA2, whose loss of function suppresses MM cells’ ability to overcome ILF2 ASO−induced DNA damage, as being essential to counteracting oxidative DNA damage. Our study reveals a mechanism of vulnerability of MM cells that have an increased demand for mitochondrial metabolism upon DNA damage activation.https://doi.org/10.1038/s41467-024-45350-8 |
| spellingShingle | Natthakan Thongon Feiyang Ma Natalia Baran Pamela Lockyer Jintan Liu Christopher Jackson Ashley Rose Ken Furudate Bethany Wildeman Matteo Marchesini Valentina Marchica Paola Storti Giannalisa Todaro Irene Ganan-Gomez Vera Adema Juan Jose Rodriguez-Sevilla Yun Qing Min Jin Ha Rodrigo Fonseca Caleb Stein Caleb Class Lin Tan Sergio Attanasio Guillermo Garcia-Manero Nicola Giuliani David Berrios Nolasco Andrea Santoni Claudio Cerchione Carlos Bueso-Ramos Marina Konopleva Philip Lorenzi Koichi Takahashi Elisabet Manasanch Gabriella Sammarelli Rashmi Kanagal-Shamanna Andrea Viale Marta Chesi Simona Colla Targeting DNA2 overcomes metabolic reprogramming in multiple myeloma Nature Communications |
| title | Targeting DNA2 overcomes metabolic reprogramming in multiple myeloma |
| title_full | Targeting DNA2 overcomes metabolic reprogramming in multiple myeloma |
| title_fullStr | Targeting DNA2 overcomes metabolic reprogramming in multiple myeloma |
| title_full_unstemmed | Targeting DNA2 overcomes metabolic reprogramming in multiple myeloma |
| title_short | Targeting DNA2 overcomes metabolic reprogramming in multiple myeloma |
| title_sort | targeting dna2 overcomes metabolic reprogramming in multiple myeloma |
| url | https://doi.org/10.1038/s41467-024-45350-8 |
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