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Multiple Myeloma, Gammopathies

RPL5 on 1p22.1 is recurrently deleted in multiple myeloma and its expression is linked to bortezomib response

Abstract

Chromosomal region 1p22 is deleted in 20% of multiple myeloma (MM) patients, suggesting the presence of an unidentified tumor suppressor. Using high-resolution genomic profiling, we delimit a 58 kb minimal deleted region (MDR) on 1p22.1 encompassing two genes: ectopic viral integration site 5 (EVI5) and ribosomal protein L5 (RPL5). Low mRNA expression of EVI5 and RPL5 was associated with worse survival in diagnostic cases. Patients with 1p22 deletion had lower mRNA expression of EVI5 and RPL5, however, 1p22 deletion status is a bad predictor of RPL5 expression in some cases, suggesting that other mechanisms downregulate RPL5 expression. Interestingly, RPL5 but not EVI5 mRNA levels were significantly lower in relapsed patients responding to bortezomib and; both in newly diagnosed and relapsed patients, bortezomib treatment could overcome their bad prognosis by raising their progression-free survival to equal that of patients with high RPL5 expression. In conclusion, our genetic data restrict the MDR on 1p22 to EVI5 and RPL5 and although the role of these genes in promoting MM progression remains to be determined, we identify RPL5 mRNA expression as a biomarker for initial response to bortezomib in relapsed patients and subsequent survival benefit after long-term treatment in newly diagnosed and relapsed patients.

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Acknowledgements

IH is a recipient of an IWT strategisch basisonderzoek PhD fellowship. PVDB is FWO senior clinical investigator. This research was funded by an ERC starting grant (n°334946), FWO funding (G067015N and G084013N) and a Stichting Tegen Kanker grant (grant n° 2012-176) to KDK. We like to thank Rowan Kuiper for bio-informatic advice.

Author contributions

IH designed and performed experiments and wrote the manuscript. MVD and PS performed outcome and gene expression analyses and critically reviewed the manuscript. EDB designed research and performed experiments. LF helped with bio-informatic analyses. GM provided survival and expression data and critically reviewed the manuscript. E Geerdens performed copy number arrays. EG, CM and AA performed MLPA. HL performed FISH. IW designed FISH, wrote and critically reviewed the manuscript. MD, LM and PVDB collected patient samples and critically reviewed the manuscript. KVDK designed research and performed supervision. KDK designed and performed research, supervised the entire study and wrote the manuscript.

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Correspondence to K De Keersmaecker.

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GM discloses employment with Takeda Pharmaceuticals International Co.

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Hofman, I., van Duin, M., De Bruyne, E. et al. RPL5 on 1p22.1 is recurrently deleted in multiple myeloma and its expression is linked to bortezomib response. Leukemia 31, 1706–1714 (2017). https://doi.org/10.1038/leu.2016.370

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