Amplification of 1q21 occurs in approximately 30% of de novo and 70% of relapsed multiple myeloma (MM) and is correlated with disease progression and drug resistance. Here, we provide evidence that the 1q21 amplification-driven overexpression of ILF2 in MM promotes tolerance of genomic instability and drives resistance to DNA-damaging agents. Mechanistically, elevated ILF2 expression exerts resistance to genotoxic agents by modulating YB-1 nuclear localization and interaction with the splicing factor U2AF65, which promotes mRNA processing and the stabilization of transcripts involved in homologous recombination in response to DNA damage. The intimate link between 1q21-amplified ILF2 and the regulation of RNA splicing of DNA repair genes may be exploited to optimize the use of DNA-damaging agents in patients with high-risk MM.
ILF2 Is a Regulator of RNA Splicing and DNA Damage Response in 1q21-Amplified Multiple Myeloma / Marchesini, Matteo; Ogoti, Yamini; Fiorini, Elena; Aktas Samur, Anil; Nezi, Luigi; D'Anca, Marianna; Storti, Paola; Samur, Mehmet Kemal; Ganan gomez, Irene; Fulciniti, Maria Teresa; Mistry, Nipun; Jiang, Shan; Bao, Naran; Marchica, Valentina; Neri, Antonino; Bueso ramos, Carlos; Wu, Chang jiun; Zhang, Li; Liang, Han; Peng, Xinxin; Giuliani, Nicola; Draetta, Giulio; Clise dwyer, Karen; Kantarjian, Hagop; Munshi, Nikhil; Orlowski, Robert; Garcia manero, Guillermo; Depinho, Ronald A.; Colla, Simona. - In: CANCER CELL. - ISSN 1535-6108. - 32:1(2017), pp. 88-100.e6. [10.1016/j.ccell.2017.05.011]
ILF2 Is a Regulator of RNA Splicing and DNA Damage Response in 1q21-Amplified Multiple Myeloma
MARCHESINI, MATTEO;STORTI, Paola;MARCHICA, VALENTINA;GIULIANI, Nicola;COLLA, Simona
2017-01-01
Abstract
Amplification of 1q21 occurs in approximately 30% of de novo and 70% of relapsed multiple myeloma (MM) and is correlated with disease progression and drug resistance. Here, we provide evidence that the 1q21 amplification-driven overexpression of ILF2 in MM promotes tolerance of genomic instability and drives resistance to DNA-damaging agents. Mechanistically, elevated ILF2 expression exerts resistance to genotoxic agents by modulating YB-1 nuclear localization and interaction with the splicing factor U2AF65, which promotes mRNA processing and the stabilization of transcripts involved in homologous recombination in response to DNA damage. The intimate link between 1q21-amplified ILF2 and the regulation of RNA splicing of DNA repair genes may be exploited to optimize the use of DNA-damaging agents in patients with high-risk MM.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
