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Cancer Cell. 2017 Jul 10;32(1):88-100.e6. doi: 10.1016/j.ccell.2017.05.011. Epub 2017 Jun 29.

ILF2 Is a Regulator of RNA Splicing and DNA Damage Response in 1q21-Amplified Multiple Myeloma.

Author information

1
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
2
Department of Biostatistics and Computational Biology, Dana Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA.
3
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
4
Department of Clinical and Experimental Medicine, University of Parma, Parma 43100, Italy.
5
LeBow Institute for Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA.
6
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
7
Department of Oncology and Hemato-Oncology, University of Milano, Milan 20122, Italy.
8
Department of Hematopathology, The University of Texas MD Cancer Center, Houston, TX 77030, USA.
9
Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
10
Department of Lymphoma/Myeloma, The University of Texas MD Cancer Center, Houston, TX 77030, USA.
11
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
12
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: scolla@mdanderson.org.

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.

KEYWORDS:

1q21 amplification; DNA damage; DNA repair; ILF2; multiple myeloma; splicing

PMID:
28669490
PMCID:
PMC5593798
DOI:
10.1016/j.ccell.2017.05.011
[Indexed for MEDLINE]
Free PMC Article

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