AGE-RELATED ALTERATIONS IN ERYTHROID AND GRANULOPOIETIC PROGENITORS IN DIAMOND-BLACKFAN ANEMIA

Mechanisms involved in the erythroid failure characterizing Diamond-Bl ackfan anaemia (DBA) remain unidentified. The general consensus is tha t 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 heterogen eity, we examined the in vitro response of erythroid progenitors CFU-E (colony-forming unit-erythroid) and BFU-E (burst-forming unit-erythro id) 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 betwe en the age of the patient and the extent of the abnormalities detected in vitro. Therefore, despite profound anaemia, 80% (7/10) of the pati ents studied within 1 year of diagnosis had normal numbers of both CFU -E and BFU-E which exhibited a normal response to cytokines. In contra st, 12/14 patients followed up for more than 3 years had decreased num bers of erythroid progenitors, in seven cases associated with decrease d colony-forming unit granulocyte-macrophage (CFU-GM). The number of C FU-E and BFU-E was not normalized even by the addition of high concent rations of combined Epo, IL-3 and SCF. These data strongly support the idea that the haemopoietic defect in DBA involves a pluripotent proge nitor and worsens with time: it is masked by the culture conditions at the onset of the disease, whereas overt expression of intrinsic alter ations occurs only at later stages of the disease and these are not re stricted to the erythroid lineage.