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.
Highlights
Diamond Blackfan anaemia (DBA) is a congenital bone marrow failure syndrome characterised by selective red cell hypoplasia
We report that ribosomal protein (RP)-mutated lymphoblastoid cell lines (LCLs) established from DBA patients show defective ribosomal RNA (rRNA) processing and ribosomal stress features such as reduced proliferation, decreased protein synthesis, and activation of p53 and its target p21
To search for potential biomarkers for the disease, we analysed the expression of AMP-activated protein kinase (AMPK), a protein involved in ribosomal stress[31], and MDM2, an important negative regulator of p5332
Summary
Diamond Blackfan anaemia (DBA) is a congenital bone marrow failure syndrome characterised by selective red cell hypoplasia. 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. Lymphoblastoid cell lines (LCLs) established from DBA patients have been used previously to study aberrant rRNA processing[7,8,9,30] Other features of these cells, such as protein synthesis rates and activation of the p53 pathway have not yet been studied in detail. We characterise the phenotype of RP mutated LCLs obtained from DBA patients and suggest that they may be useful for molecular and pharmacological investigations
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