A novel mouse model to study the effects of new therapies for Diamond-Blackfan anemia

Diamond-Blackfan anemia (DBA) is an inherited bone marrow (BM) failure characterized by macrocytic anemia, congenital malformations, and an increased predisposition to cancer. 1,2More than 90% of patients with DBA are diagnosed within the first year of life (median age, 12 weeks). 3The pathogenesis of DBA is linked to loss-of-function mutations in genes that encode ribosomal proteins (RPs), although mutations in 3 non-RP genes (GATA1, TSR2, and HEATR3) have been reported. 1,[4][5]5][6] Mutations in RPS19, RPL5, RPS26, RPL11, RPL35a, RPS10, RPS24, and RPS17 are responsible for ~70% of the patients with DBA.Varying degrees of anemia are observed in 90% of patients with DBA at diagnosis and are the primary reason for treatment, which includes corticosteroids or red blood cell (RBC) transfusions.However, lifelong treatment results in morbidities, such as osteoporosis, diabetes, and iron overload. 1,2,7Currently, hematopoietic stem cell transplantation is the only curative therapy. 3,8The challenge in conducting preclinical studies for new therapies to treat DBA is the lack of mouse models that recapitulate its clinical features, including haploinsufficiency of ribosomal genes, severe anemia, and age of onset.Heterozygous mutations in RPL11 are found in 5% to 7% of patients with DBA. 1,2reviously published mouse models with Rpl11 haploinsufficiency have mild anemia and a normal life span, 9,10 which have limitations for therapeutics development.