ILF2 Is Upregulated by 1q21 Amplification in Multiple Myeloma

Chromosome 1q21 is amplified in 30% of de novo and 70% of relapsed multiple myeloma and is associated with a poor outcome and drug resistance. The 1q21 amplicon contains a number of candidate genes, and it is not clear which of these genes contribute to high-risk multiple myeloma. Thus, Marchesini and colleagues performed an shRNA screen to identify candidate drivers in 1q21 whose loss of unction results in selective cell death or growth inhibition in 1q21-amplified multiple myeloma cells. ILF2 emerged as the top hit, and its depletion extended survival in xenograft models in vivo. ILF2 encodes the regulatory subunit of the NF90/NF110 complexes, which are involved in mitotic control. Accordingly, ILF2 depletion in 1q21-amplified multiple myeloma cells resulted in an increase in multinucleated cells and abnormal nuclear morphologies, such as nucleoplasmic bridges, nuclear buds, and micronuclei, suggesting DNA damage–induced genomic instability. Further, ILF2 depletion suppressed homologous recombination (HR) and increased DNA double-strand breaks. Consistent with these findings, depletion of ILF2 increased the sensitivity to the DNA-damaging agent melphalan, which is used for the treatment of multiple myeloma, suggesting that overexpression of ILF2 in 1q21-amplified multiple myeloma may regulate DNA damage repair to promote drug resistance. Mechanistically, DNA damage induced binding of ILF2 to the DNA/RNA-binding protein YB1, increasing YB1 nuclear localization and promoting its interaction with the splicing factor U2AF65, which led to increased splicing of genes involved in DNA repair. The finding that DNA damage activates ILF2/YB1 signaling to regulate splicing and ensure stability of genes directly involved in DNA double strand break repair suggests a mechanism by which 1q21 amplification–induced ILF2 overexpression may promote resistance to DNA-damaging agents in patients with multiple myeloma.

Marchesini M, Ogoti Y, Fiorini E, Samur AA, Nezi L, D'Anca M, et al. ILF2 is a regulator of RNA splicing and DNA damage response in 1q21-amplified multiple myeloma. Cancer Cell 20172017;32:88–100.e6.

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