Nature Communications (Feb 2024)
Targeting DNA2 overcomes metabolic reprogramming in multiple myeloma
- 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
Affiliations
- Natthakan Thongon
- Department of Leukemia, The University of Texas MD Anderson Cancer Center
- Feiyang Ma
- Division of Rheumatology, Department of Internal Medicine, Michigan Medicine, University of Michigan
- Natalia Baran
- Department of Leukemia, The University of Texas MD Anderson Cancer Center
- Pamela Lockyer
- Department of Leukemia, The University of Texas MD Anderson Cancer Center
- Jintan Liu
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center
- Christopher Jackson
- Department of Leukemia, The University of Texas MD Anderson Cancer Center
- Ashley Rose
- Department of Leukemia, The University of Texas MD Anderson Cancer Center
- Ken Furudate
- Department of Leukemia, The University of Texas MD Anderson Cancer Center
- Bethany Wildeman
- Department of Leukemia, The University of Texas MD Anderson Cancer Center
- Matteo Marchesini
- IRCCS Instituto Romagnolo per lo Studio dei Tumori (IRST) Dino Amadori
- Valentina Marchica
- Department of Medicine and Surgery, University of Parma
- Paola Storti
- Department of Medicine and Surgery, University of Parma
- Giannalisa Todaro
- Department of Medicine and Surgery, University of Parma
- Irene Ganan-Gomez
- Department of Leukemia, The University of Texas MD Anderson Cancer Center
- Vera Adema
- Department of Leukemia, The University of Texas MD Anderson Cancer Center
- Juan Jose Rodriguez-Sevilla
- Department of Leukemia, The University of Texas MD Anderson Cancer Center
- Yun Qing
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center
- Min Jin Ha
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center
- Rodrigo Fonseca
- Department of Medicine, Mayo Clinic
- Caleb Stein
- Department of Medicine, Mayo Clinic
- Caleb Class
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Butler University
- Lin Tan
- Metabolomics Core Facility, Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center
- Sergio Attanasio
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center
- Guillermo Garcia-Manero
- Department of Leukemia, The University of Texas MD Anderson Cancer Center
- Nicola Giuliani
- Department of Medicine and Surgery, University of Parma
- David Berrios Nolasco
- Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center
- Andrea Santoni
- Department of Leukemia, The University of Texas MD Anderson Cancer Center
- Claudio Cerchione
- IRCCS Instituto Romagnolo per lo Studio dei Tumori (IRST) Dino Amadori
- Carlos Bueso-Ramos
- Department of Hemopathology, The University of Texas MD Anderson Cancer Center
- Marina Konopleva
- Department of Leukemia, The University of Texas MD Anderson Cancer Center
- Philip Lorenzi
- Metabolomics Core Facility, Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center
- Koichi Takahashi
- Department of Leukemia, The University of Texas MD Anderson Cancer Center
- Elisabet Manasanch
- Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center
- Gabriella Sammarelli
- Department of Medicine and Surgery, University of Parma
- Rashmi Kanagal-Shamanna
- Department of Hemopathology, The University of Texas MD Anderson Cancer Center
- Andrea Viale
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center
- Marta Chesi
- Department of Medicine, Mayo Clinic
- Simona Colla
- Department of Leukemia, The University of Texas MD Anderson Cancer Center
- DOI
- https://doi.org/10.1038/s41467-024-45350-8
- Journal volume & issue
-
Vol. 15,
no. 1
pp. 1 – 13
Abstract
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.
