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 and Simona Colla ()
Additional contact information
Natthakan Thongon: The University of Texas MD Anderson Cancer Center
Feiyang Ma: University of Michigan
Natalia Baran: The University of Texas MD Anderson Cancer Center
Pamela Lockyer: The University of Texas MD Anderson Cancer Center
Jintan Liu: The University of Texas MD Anderson Cancer Center
Christopher Jackson: The University of Texas MD Anderson Cancer Center
Ashley Rose: The University of Texas MD Anderson Cancer Center
Ken Furudate: The University of Texas MD Anderson Cancer Center
Bethany Wildeman: The University of Texas MD Anderson Cancer Center
Matteo Marchesini: IRCCS Instituto Romagnolo per lo Studio dei Tumori (IRST) Dino Amadori
Valentina Marchica: University of Parma
Paola Storti: University of Parma
Giannalisa Todaro: University of Parma
Irene Ganan-Gomez: The University of Texas MD Anderson Cancer Center
Vera Adema: The University of Texas MD Anderson Cancer Center
Juan Jose Rodriguez-Sevilla: The University of Texas MD Anderson Cancer Center
Yun Qing: The University of Texas MD Anderson Cancer Center
Min Jin Ha: The University of Texas MD Anderson Cancer Center
Rodrigo Fonseca: Mayo Clinic
Caleb Stein: Mayo Clinic
Caleb Class: Butler University
Lin Tan: The University of Texas MD Anderson Cancer Center
Sergio Attanasio: The University of Texas MD Anderson Cancer Center
Guillermo Garcia-Manero: The University of Texas MD Anderson Cancer Center
Nicola Giuliani: University of Parma
David Berrios Nolasco: The University of Texas MD Anderson Cancer Center
Andrea Santoni: The University of Texas MD Anderson Cancer Center
Claudio Cerchione: IRCCS Instituto Romagnolo per lo Studio dei Tumori (IRST) Dino Amadori
Carlos Bueso-Ramos: The University of Texas MD Anderson Cancer Center
Marina Konopleva: The University of Texas MD Anderson Cancer Center
Philip Lorenzi: The University of Texas MD Anderson Cancer Center
Koichi Takahashi: The University of Texas MD Anderson Cancer Center
Elisabet Manasanch: The University of Texas MD Anderson Cancer Center
Gabriella Sammarelli: University of Parma
Rashmi Kanagal-Shamanna: The University of Texas MD Anderson Cancer Center
Andrea Viale: The University of Texas MD Anderson Cancer Center
Marta Chesi: Mayo Clinic
Simona Colla: The University of Texas MD Anderson Cancer Center

Nature Communications, 2024, vol. 15, issue 1, 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.

Date: 2024
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DOI: 10.1038/s41467-024-45350-8

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