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.

中文翻译：

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ILF2是1q21扩增的多发性骨髓瘤中RNA剪接和DNA损伤反应的调节剂。

1q21的扩增发生在大约30％的新生患者和70％的复发性多发性骨髓瘤（MM）中，并且与疾病进展和耐药性相关。在这里，我们提供的证据表明，MM中1q21扩增驱动的ILF2过表达促进了基因组不稳定性的耐受性，并驱动了对DNA破坏剂的抗性。从机制上讲，升高的ILF2表达通过调节YB-1核定位以及与剪接因子U2AF65的相互作用而对基因毒性剂产生抗性，从而促进mRNA加工和响应DNA损伤而参与同源重组的转录本的稳定。可以利用1q21扩增的ILF2与DNA修复基因的RNA剪接调控之间的密切联系来优化高危MM患者中DNA损伤剂的使用。