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

Matteo Marchesini; Yamini Ogoti; Elena Fiorini; Anil Aktas Samur; Luigi Nezi; Marianna D'Anca; Paola Storti; Mehmet Kemal Samur; Irene Ganan-Gomez; Maria Teresa Fulciniti; Nipun Mistry; Shan Jiang; Naran Bao; Valentina Marchica; Antonino Neri; Carlos Bueso-Ramos; Chang Jiun Wu; Li Zhang; Han Liang; Xinxin Peng; Nicola Giuliani; Giulio Draetta; Karen Clise-Dwyer; Hagop Kantarjian; Nikhil Munshi; Robert Orlowski; Guillermo Garcia-Manero; Ronald A. DePinho; Simona Colla

doi:10.1016/j.ccell.2017.05.011

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

Matteo Marchesini, Yamini Ogoti, Elena Fiorini, Anil Aktas Samur, Luigi Nezi, Marianna D'Anca, Paola Storti, Mehmet Kemal Samur, Irene Ganan-Gomez, Maria Teresa Fulciniti, Nipun Mistry, Shan Jiang, Naran Bao, Valentina Marchica, Antonino Neri, Carlos Bueso-Ramos, Chang Jiun Wu, Li Zhang, Han Liang, Xinxin PengNicola Giuliani, Giulio Draetta, Karen Clise-Dwyer, Hagop Kantarjian, Nikhil Munshi, Robert Orlowski, Guillermo Garcia-Manero, Ronald A. DePinho, Simona Colla

Research output: Contribution to journal › Article › peer-review

102 Scopus citations

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.

Original language	English (US)
Pages (from-to)	88-100.e6
Journal	Cancer cell
Volume	32
Issue number	1
DOIs	https://doi.org/10.1016/j.ccell.2017.05.011
State	Published - Jul 10 2017

Keywords

1q21 amplification
DNA damage
DNA repair
ILF2
multiple myeloma
splicing

ASJC Scopus subject areas

Oncology
Cell Biology
Cancer Research

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Marchesini, M., Ogoti, Y., Fiorini, E., Aktas Samur, A., Nezi, L., D'Anca, M., Storti, P., Samur, M. K., Ganan-Gomez, I., Fulciniti, M. T., Mistry, N., Jiang, S., Bao, N., Marchica, V., Neri, A., Bueso-Ramos, C., Wu, C. J., Zhang, L., Liang, H., ... Colla, S. (2017). ILF2 Is a Regulator of RNA Splicing and DNA Damage Response in 1q21-Amplified Multiple Myeloma. Cancer cell, 32(1), 88-100.e6. https://doi.org/10.1016/j.ccell.2017.05.011

Marchesini, M, Ogoti, Y, Fiorini, E, Aktas Samur, A, Nezi, L, D'Anca, M, Storti, P, Samur, MK, Ganan-Gomez, I, Fulciniti, MT, Mistry, N, Jiang, S, Bao, N, Marchica, V, Neri, A, Bueso-Ramos, C, Wu, CJ, Zhang, L, Liang, H, Peng, X, Giuliani, N, Draetta, G , Clise-Dwyer, K , Kantarjian, H, Munshi, N, Orlowski, R , Garcia-Manero, G , DePinho, RA & Colla, S 2017, 'ILF2 Is a Regulator of RNA Splicing and DNA Damage Response in 1q21-Amplified Multiple Myeloma', Cancer cell, vol. 32, no. 1, pp. 88-100.e6. https://doi.org/10.1016/j.ccell.2017.05.011

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title = "ILF2 Is a Regulator of RNA Splicing and DNA Damage Response in 1q21-Amplified Multiple Myeloma",

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",

author = "Matteo Marchesini and Yamini Ogoti and Elena Fiorini and {Aktas Samur}, Anil and Luigi Nezi and Marianna D'Anca and Paola Storti and Samur, {Mehmet Kemal} and Irene Ganan-Gomez and Fulciniti, {Maria Teresa} and Nipun Mistry and Shan Jiang and Naran Bao and Valentina Marchica and Antonino Neri and Carlos Bueso-Ramos and Wu, {Chang Jiun} and Li Zhang and Han Liang and Xinxin Peng and Nicola Giuliani and Giulio Draetta and Karen Clise-Dwyer and Hagop Kantarjian and Nikhil Munshi and Robert Orlowski and Guillermo Garcia-Manero and DePinho, {Ronald A.} and Simona Colla",

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doi = "10.1016/j.ccell.2017.05.011",

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AU - Marchesini, Matteo

AU - Ogoti, Yamini

AU - Fiorini, Elena

AU - Aktas Samur, Anil

AU - Nezi, Luigi

AU - D'Anca, Marianna

AU - Storti, Paola

AU - Samur, Mehmet Kemal

AU - Ganan-Gomez, Irene

AU - Fulciniti, Maria Teresa

AU - Mistry, Nipun

AU - Jiang, Shan

AU - Bao, Naran

AU - Marchica, Valentina

AU - Neri, Antonino

AU - Bueso-Ramos, Carlos

AU - Wu, Chang Jiun

AU - Zhang, Li

AU - Liang, Han

AU - Peng, Xinxin

AU - Giuliani, Nicola

AU - Draetta, Giulio

AU - Clise-Dwyer, Karen

AU - Kantarjian, Hagop

AU - Munshi, Nikhil

AU - Orlowski, Robert

AU - Garcia-Manero, Guillermo

AU - DePinho, Ronald A.

AU - Colla, Simona

PY - 2017/7/10

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N2 - 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.

AB - 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.

KW - 1q21 amplification

KW - DNA damage

KW - DNA repair

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KW - multiple myeloma

KW - splicing

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

Abstract

Keywords

ASJC Scopus subject areas

MD Anderson CCSG core facilities

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