Key Points

• GATA1 is downregulated in RPS19-deficient cells and zebrafish through upregulation of p53, TNF-a, and p38 MAPK. • Treatment of rps19-deficient zebrafish with the TNF-a inhibitor etanercept rescues their erythroid and developmental defects. Diamond-Blackfan anemia (DBA) is an inherited disorder characterized by defects in erythropoiesis, congenital abnormalities, and predisposition to cancer. Approximately 25 % of DBA patients have a mutation in RPS19, which encodes a component of the 40S ribosomal subunit. Upregulation of p53 contributes to the pathogenesis of DBA, but the link between ribosomal protein mutations and erythropoietic defects is not well under-stood.WefoundthatRPS19deficiency inhematopoieticprogenitorcells leads todecreased GATA1 expression in the erythroid progenitor population andp53-dependent upregulation of tumornecrosis factor-a (TNF-a) innonerythroidcells.Thedecrease inGATA1expression was mediated, at least in part, by activation of p38 MAPK in erythroid cells and rescued by inhibition of TNF-a or p53. The anemia phenotype in rps19-deficient zebrafish was re-versed by treatment with the TNF-a inhibitor etanercept. Our data reveal that RPS19 defi-ciency leads to inflammation, p53-dependent increase in TNF-a, activation of p38 MAPK, anddecreasedGATA1expression, suggestinganovelmechanism for the erythroiddefects observed in DBA. (Blood. 2014;124(25):3791-3798