Diamond Blackfan anemia: a model for the translational approach to understanding human disease

Abstract

Diamond Blackfan anemia (DBA) is an inherited bone marrow failure syndrome. As with the other rare inherited bone marrow failure syndromes, the study of these disorders provides important insights into basic biology and, in the case of DBA, ribosome biology; the disruption of which characterizes the disorder. Thus DBA serves as a paradigm for translational medicine in which the efforts of clinicians to manage DBA have informed laboratory scientists who, in turn, have stimulated clinical researchers to utilize scientific discovery to provide improved care. In this review we describe the clinical syndrome Diamond Blackfan anemia and, in particular, we demonstrate how the study of DBA has allowed scientific inquiry to create opportunities for progress in its understanding and treatment.

Elucidation of the EP defect in Diamond-Blackfan anemia by characterization and prospective isolation of human EPs

“…[1][2][3] Normochromic, macrocytic anemia, and reticulocytopenia, the hematologic hallmarks of DBA, stem from a selective paucity of erythroid precursors in the BM. 4 Animal models of DBA and in vitro studies of human unfractionated BM or total CD34…”

“…5,6 This defect has been defined functionally by a reduced ability of DBA BM to generate erythroid burst-forming unit (BFU-E) and erythroid colony-forming unit (CFU-E) colonies. 7,8 Since DBA EP have also been reported to have qualitative abnormalities, such as relative erythropoietin insensitivity, 9,10 elucidation of the relative roles of these qualitative and quantitative defects in DBA erythropoiesis and determination of the mechanism of steroid responsiveness in 40% patients, 4 require knowledge of the markers that define the BM cells giving rise to CFU-E and BFU-E. Although in mice the immunophenotypes of such cells have been described in fetal liver, 11,12 facilitating important insights into erythropoiesis, 12,13 in humans, definitions of corresponding EPs are limited, thus precluding their direct study in normal and aberrant erythropoiesis.…”

Society for Pediatric Research 2015 Young Investigator Award: genetics of human hematopoiesis—what patients can teach us about blood cell production

“…This disease is caused by autosomal dominant mutations in one of 17 different ribosomal protein genes (14). Such mutations account for approximately 60-70% of cases of this disorder.…”

“…For example, mice with mutations in Sec23b, whose orthologue is known to cause congenital dyserythropoietic anemia type II in humans, have completely normal blood counts and ostensibly normal red blood cell production (erythropoiesis) (11)(12)(13). In addition, there has also been an inability to develop faithful models for other congenital forms of anemia, such as Diamond-Blackfan anemia, which is characterized by a paucity of the earliest identifiable erythroid precursors with a reduction in erythroid-committed progenitors as well (14). At the genomic level, gene expression and histone modifications show global divergence at comparable stages of mouse and human erythropoiesis (6)(7)(8)10).…”

A Novel Mutation of Ribosomal Protein S19 Gene in a Chinese Child with Diamond-Blackfan Anemia

“…Diamond-Blackfan anemia (DBA; OMIM 205900) is a rare congenital erythroid aplasia that usually presents in infancy [1]. The anemia is discovered early in life, usually within the first 2 years; diagnosis after 4 years of age is very unlikely.…”