Lymphoblastoid cell lines from Diamond Blackfan anaemia patients exhibit a full ribosomal stress phenotype that is rescued by gene therapy.

Abstract

Diamond Blackfan anaemia (DBA) is a congenital bone marrow failure syndrome characterised by selective red cell hypoplasia. DBA is most often due to heterozygous mutations in ribosomal protein (RP) genes that lead to defects in ribosome biogenesis and function and result in ribosomal stress and p53 activation. The molecular mechanisms underlying this pathology are still poorly understood and studies on patient erythroid cells are hampered by their paucity. Here we report that RP-mutated lymphoblastoid cell lines (LCLs) established from DBA patients show defective rRNA processing and ribosomal stress features such as reduced proliferation, decreased protein synthesis, and activation of p53 and its target p21. These phenotypic alterations were corrected by gene complementation. Our data indicate that DBA LCLs could be a useful model for molecular and pharmacological investigations.

• Authors: Anna Aspesi, Valentina Monteleone, Marta Betti, Chiara Actis, Giulia Morleo, Marika Sculco, Simonetta Guarrera, Marcin W Wlodarski, Ugo Ramenghi, Claudio Santoro, Steven R Ellis, Fabrizio Loreni, Antonia Follenzi, Irma Dianzani
• Journal: Scientific reports (Sci Rep) Vol. 7 Issue 1 Pg. 12010 (09 20 2017) ISSN: 2045-2322 [Electronic] England
• PMID: 28931864 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cyclin-Dependent Kinase Inhibitor p21
• RNA, Ribosomal
• Ribosomal Proteins
• Tumor Suppressor Protein p53

Topics

• Anemia, Diamond-Blackfan (genetics, metabolism, therapy)
• Cell Line
• Cell Proliferation (genetics)
• Cyclin-Dependent Kinase Inhibitor p21 (genetics, metabolism)
• Genetic Therapy
• Humans
• Mutation
• Phenotype
• RNA, Ribosomal (genetics, metabolism)
• Ribosomal Proteins (genetics, metabolism)
• Ribosomes (genetics, metabolism)
• Tumor Suppressor Protein p53 (genetics, metabolism)