Targeting DNA2 overcomes metabolic reprogramming in multiple myeloma
Natthakan Thongon, Feiyang Ma, Natalia Baran, Pamela Lockyer, Jintan Liu, C. Ellen Jackson, Ashley Rose, Ken Furudate, Bethany Wildeman, Matteo Marchesini, Valentina Marchica, Paola Storti, Giannalisa Todaro, Irene Gañán‐Gómez, Vera Ademà, Juan José Rodríguez‐Sevilla, Yun Qing, Min Jin Ha, Rodrigo Fonseca, Caleb K. Stein, Caleb A. Class, Lin Tan, Sergio Attanasio, Guillermo Garcia‐Manero, Nicola Giuliani, David Berrios Nolasco, Andrea Santoni, Claudio Cerchione, Carlos E. Bueso‐Ramos, Marina Konopleva, Philip L. Lorenzi, Koichi Takahashi, Elisabet E. Manasanch, Gabriella Sammarelli, Rashmi Kanagal‐Shamanna, Andrea Viale, Marta Chesi, Simona Colla
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.