Diamond-Blackfan Anemia: Erythropoiesis Lost in Translation

Abstract: Diamond-Blackfan anemia (DBA) is a congenital erythroid aplasia that usually presents as macrocytic anemia during infancy. Linkage analysis suggests that at least four genes are associated with DBA of which two have been identified so far. The known DBA genes encode the ribosomal proteins S19 and S24 accounting for 25% and 2% of the patients respectively. This study shows that RPS19 gene transfer improves the proliferation defect and erythroid development in RPS19 deficient DBA patient CD34+ cells in vitro. These results indicate that RPS19-deficient DBA patients are potential candidates for gene therapy. We next created two disease models for RPS19-deficient DBA. We were able to induce a DBA phenotype in normal cells by reducing RPS19 expression using RNA interference (RNAi) to silence RPS19 expression in human CD34+ BM cells. Analogous in vitro DBA models were created using erythroid leukemia TF-1 and UT7 cell lines that harbor Doxycycline-dependent RNAi-mediated RPS19 silencing. When induced to silence RPS19 expression, TF-1 cell proliferation decreased together with a marked reduction in the number of erythroid cells. The DBA disease model cell lines were next used in a study showing that RPS19-deficient TF-1 cells and DBA patient cells share a defect in 18S rRNA processing which ultimately hampers ribosomal 40S subunit maturation. We predict that these RPS19-deficient cell lines can be used for further mechanistic studies on RPS19 deficiency in erythropoiesis. The study is concluded by a discussion where links between ribosomal proteins and erythropoiesis are reviewed together with considerations regarding future directions of DBA research.