Age‐related alterations in erythroid and granulopoietic progenitors in Diamond‐Blackfan anaemia

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Abstract
SUMMARY. Mechanisms involved in the erythroid failure characterizing Diamond‐Blackfan anaemia (DBA) remain unidentified. The general consensus is that the defect is intrinsic to the marrow erythroid progenitor, but the target progenitor cell has not been precisely identified, and in vitro studies have revealed considerable heterogeneity between patients. In order to understand better the meaning of such a biological heterogeneity, we examined the in vitro response of erythroid progenitors CFU‐E (colony‐forming unit‐erythroid) and BFU‐E (burst‐forming unit‐erythroid) to erythropoietin (Epo), interleukin‐3 (IL‐3) and stem cell factor (SCF) in a large series of 24 patients from 1 month to over 20 years of age. Results of colony assays revealed a striking correlation between the age of the patient and the extent of the abnormalities detected in vitro. Therefore, despite profound anaemia, 80% (7/10) of the patients studied within 1 year of diagnosis had normal numbers of both CFU‐E and BFU‐E which exhibited a normal response to cytokines. In contrast, 12/14 patients followed up for more than 3 years had decreased numbers of erythroid progenitors, in seven cases associated with decreased colony‐forming unit granulocyte‐macrophage (CFU‐GM). The number of CFU‐E and BFU‐E was not normalized even by the addition of high concentrations of combined Epo, IL‐3 and SCF. These data strongly support the idea that the haemopoietic defect in DBA involves a pluripotent progenitor and worsens with time: it is masked by the culture conditions at the onset of the disease, whereas overt expression of intrinsic alterations occurs only at later stages of the disease and these are not restricted to the erythroid lineage.