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Emerging drug class may enhance red blood cell production in anemic patients
Date:12/22/2010

d cells, called burst forming unit-erythroids (BFU-Es) and colony forming unit-erythroids (CFU-Es), from mouse fetal liver cells. During erythropoiesis, BFU-Es produce CFU-Es, which are then stimulated by EPO to generate the pro-erythroblasts that eventually become red blood cells. By dividing numerous times before maturing, both BFU-Es and CFU-Es have a limited ability to self-renew. When Flygare exposed BFU-Es and CFU-Es in vitro to a corticosteroid, only the BFU-Es responded--dividing 13 times instead of the usual 9 times before maturing into CFU-Es. These additional cell divisions ultimately led to a 13-fold increase in red blood-cell production.

Flygare identified 83 genes in BFU-Es that are stimulated by the corticosteroid, and he examined the promoters that facilitate those genes' transcription. The promoters appeared to have binding sites for a transcription factor, called hypoxia-induced factor 1-alpha (HIF1-alpha), that is activated when an organism is deprived of oxygen. To prolong the 83 genes' promotion by HIF1-alpha, Flygare used a class of drugs known as prolyl hydroxylase inhibitors (PHIs), which extends HIF1-alpha's effectiveness. PHIs have also been used in early-stage clinical trials to increase EPO production.

When Flygare added both a corticosteroid and a PHI to BFU-Es in culture, the cells produced 300 times more red blood cells than did cells without exposure to the drugs. Flygare repeated the experiment with adult human BFU-Es, and found that a corticosteroid plus a PHI generated 10 times more red blood cells than BFU-Es exposed to a corticosteroid alone.

Flygare hopes this research eventually leads to improved treatment for DBA patients who currently suffer from a host of corticosteroid-induced side effects, including decreased bone density, immunosuppression, stunted growth, and cataracts.

"If you could lower the dose of steroids so DBA patients would get just a little bit, and then add on this kind of
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Contact: Nicole Giese
giese@wi.mit.edu
617-258-6851
Whitehead Institute for Biomedical Research
Source:Eurekalert

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