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Summary  Diamond–Blackfan anaemia ( DBA ) is a rare congenital disease causing severe anaemia and progressive bone marrow failure. The majority of patients carry mutations in ribosomal proteins, which leads to depletion of erythroid progenitors in the bone marrow. As many as 40% of all  DBA  patients receive glucocorticoids to alleviate their anaemia. However, despite their use in  DBA  treatment for more than half a century, the therapeutic mechanisms of glucocorticoids remain largely unknown. Therefore we sought to study disease specific effects of glucocorticoid treatment using a ribosomal protein s19 ( Rps19 ) deficient mouse model of  DBA . This study determines for the first time that a mouse model of  DBA  can respond to glucocorticoid treatment, similar to  DBA  patients. Our results demonstrate that glucocorticoid treatment reduces apoptosis, rescues erythroid progenitor depletion and premature differentiation of erythroid cells. Furthermore, glucocorticoids prevent  Trp53  activation in  Rps19 ‐deficient cells‐ in a disease‐specific manner. Dissecting the therapeutic mechanisms behind glucocorticoid treatment of  DBA  provides indispensible insight into  DBA  pathogenesis. Identifying mechanisms important for  DBA  treatment also enables development of more disease‐specific treatments of  DBA .

Glucocorticoids improve erythroid progenitor maintenance and dampen Trp53 response in a mouse model of Diamond–Blackfan anaemia