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Blood, 15 January 2005, Vol. 105, No. 2, pp. 838-846.
Prepublished online as a Blood First Edition Paper on July 6, 2004; DOI 10.1182/blood-2004-03-1016.
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Submitted March 17, 2004
Accepted June 14, 2004
Two-phase culture in Diamond Blackfan Anemia: localization of erythroid defect
Yaw Ohene-Abuakwa, Karen A Orfali, Carine Marius, and Sarah E Ball*
Cellular and Molecular Medicine (Haematology), St George's Hospital Medical School, London, United Kingdom
* Corresponding author; email: sball{at}sghms.ac.uk.
The erythroid defect in Diamond Blackfan Anemia (DBA) is known to be intrinsic to the stem cell, but its molecular pathophysiology remains obscure. Using a 2-phase liquid erythroid culture system we have demonstrated a consistent defect in DBA, irrespective of clinical severity. The same abnormality was observed in cultures from first-degree relatives with isolated increased eADA activity. DBA cultures were indistinguishable from controls until the end of erythropoietin (Epo)-free phase I, but failed to demonstrate the normal synchronised wave of erythroid expansion and terminal differentiation on exposure to Epo. Dexamethasone increased Epo sensitivity of erythroid progenitor cells and enhanced erythroid expansion in phase II in both normal and DBA cultures. In DBA cultures treated with dexamethasone, Epo sensitivity was comparable to normal, but erythroid expansion remained subnormal. In clonogenic phase II cultures, the number of colonies did not significantly differ between normal and DBA, in the presence or absence of dexamethasone, and at both low and high Epo concentrations. However, colonies were markedly smaller in DBA under all conditions. This suggests that the Epo-triggered onset of terminal maturation is intact in DBA, and the defect lies downstream of the Epo receptor, influencing survival and/or proliferation of erythroid progenitors.
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