title: 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.
authors.affiliation: KU Leuven - University of Leuven, Department of Oncology, LKI - Leuven Cancer Institute, Leuven, Belgium.
authors.forename: I J F
authors.initials: IJF
authors.lastname: Hofman
authors.affiliation: Department of Hematology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: van Duin
authors.affiliation: Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussels (VUB), Brussels, Belgium.
authors.forename: E
authors.initials: E
authors.lastname: De Bruyne
authors.affiliation: KU Leuven - University of Leuven, Department of Oncology, LKI - Leuven Cancer Institute, Leuven, Belgium.
authors.forename: L
authors.initials: L
authors.lastname: Fancello
authors.affiliation: Takeda Pharmaceuticals International Co., Cambridge, MA, USA.
authors.forename: G
authors.initials: G
authors.lastname: Mulligan
authors.affiliation: Center for Human Genetics, KU Leuven - University of Leuven, Center for Human Genetics, LKI - Leuven Cancer Institute, Leuven, Belgium.|Center for the Biology of Disease, VIB Center for the Biology of Disease, Leuven, Belgium.
authors.forename: E
authors.initials: E
authors.lastname: Geerdens
authors.affiliation: Dipartimento Scienze della Sanità Pubblica e Pediatriche, Univ.Torino, Torino, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Garelli
authors.affiliation: Dipartimento di Scienze Mediche, Univ.Torino, Torino, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Mancini
authors.affiliation: Center for Human Genetics, University Hospitals Leuven, Leuven, Belgium.
authors.forename: H
authors.initials: H
authors.lastname: Lemmens
authors.affiliation: Department of Hematology, University Hospital Leuven, Leuven, Belgium.
authors.forename: M
authors.initials: M
authors.lastname: Delforge
authors.affiliation: Center for Human Genetics, University Hospitals Leuven, Leuven, Belgium.
authors.forename: P
authors.identifier: 0000-0003-4719-1935
authors.initials: P
authors.lastname: Vandenberghe
authors.affiliation: Center for Human Genetics, KU Leuven - University of Leuven, Center for Human Genetics, LKI - Leuven Cancer Institute, Leuven, Belgium.
authors.forename: I
authors.initials: I
authors.lastname: Wlodarska
authors.affiliation: Department of Health Sciences, Universita' del Piemonte Orientale, Novara, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Aspesi
authors.affiliation: Center for Human Genetics, University Hospitals Leuven, Leuven, Belgium.
authors.forename: L
authors.initials: L
authors.lastname: Michaux
authors.affiliation: Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussels (VUB), Brussels, Belgium.
authors.forename: K
authors.initials: K
authors.lastname: Vanderkerken
authors.affiliation: Department of Hematology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: P
authors.initials: P
authors.lastname: Sonneveld
authors.affiliation: KU Leuven - University of Leuven, Department of Oncology, LKI - Leuven Cancer Institute, Leuven, Belgium.
authors.forename: K
authors.identifier: 0000-0002-7420-9531
authors.initials: K
authors.lastname: De Keersmaecker
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000069286:Bortezomib / Q000627:therapeutic use*; D002872:Chromosome Deletion; D002878:Chromosomes, Human, Pair 1; D004268:DNA-Binding Proteins / Q000235:genetics; D016147:Genes, Tumor Suppressor; D006801:Humans; D000074008:MDS1 and EVI1 Complex Locus Protein; D009101:Multiple Myeloma / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D009154:Mutation; D011519:Proto-Oncogenes / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D012269:Ribosomal Proteins / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D000074008:MDS1 and EVI1 Complex Locus Protein; C063575:MECOM protein, human; D012333:RNA, Messenger; D012269:Ribosomal Proteins; D014157:Transcription Factors; C549166:ribosomal protein L5, human; D000069286:Bortezomib