Abstract 3595: Riboprotein variant and their role in chondrogenic differentiation and osteosarcoma development

Abstract

Abstract Variants in genes encoding ribosomal proteins (RPs) have thus far been associated with Diamond-Blackfan anemia, a rare inherited bone marrow failure, and isolated congenital asplenia. We reported recently one de novo missense variant and three de novo splice variants in the RPL13 gene, which encodes ribosomal protein RPL13/eL13, in four unrelated individuals with a rare bone dysplasia causing severe short stature. The three splice variants (c.477+1G>T, c.477+1G>A, and c.477+2 T>C) result in partial intron retention, which leads to an 18-amino acid insertion. These RPL13 variants define a human ribosomopathy leading to a rare skeletal dysplasia and highlight the role of this ribosomal protein in bone development. It has been shown that patients suffering from ribosomopathies have a highly predisposition to develop cancer compared to general population. Moreover, recent studies have also revealed that mutations in factors involved in ribosome synthesis appear to be drivers of tumorigenesis in sporadic cancers. In this study, we focused on the role of variants of the riboprotein RPL13 in the bone biology and in the development of osteosarcoma. Mesenchymal stem cells expressing variants of RPL13 or wild type RPL13 have been cultured for chondrogenic and osteoblastic differentiation. Our results show that RPL13 variants did not modified the capacity of cells to differentiate into osteoblasts. However, the chondrogenic differentiation was increased in cells expressing variants of RPL13. The expression of sox9 and collagen type X were investigated by immunochemistry on chondrocyte micromass and revealed an increase of expression of these markers in RPL13 variants cells. We next investigated the role of variants of RPL13 in osteosarcoma cell lines. Several cell lines were transduced by lentiviral vector to produce variants of RPL13. The variants induced an increase of cell proliferation and survival. The clonogenecity and the invasion have been also studied. Taken together, these data show that variants of a gene encoding for a riboprotein causing a ribosomopathy could have an effect on chondrogenic differentiation and on osteosarcoma development. Citation Format: Emilien Orgebin, Benjamin Ory, Francois Lamoureux, Marie-Francoise O'Donohue, Céline Charrier, Pierre-Emmanuel Gleizes, Bertrand Isidor, Marc Baud'huin. Riboprotein variant and their role in chondrogenic differentiation and osteosarcoma development [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3595.