Hydroxyurea reduces the levels of the fetal globin gene repressors ZBTB7A/LRF and BCL11A in erythroid cells in vitro

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Abstract
Hydroxyurea (also known as hydroxycarbamide) has been the most widely used treatment for children and adults with sickle cell disease since the 1980s. It is thought to act primarily by boosting the expression of fetal globin. The molecular mechanism through which hydroxyurea elevates fetal globin levels has not been understood and we have explored this question here. It has recently been established that expression of the fetal globin gene is directly inhibited by two DNA-binding proteins, the transcriptional repressors ZBTB7A and BCL11A. We therefore tested—in primary human erythroid cells in culture and in cell lines—whether hydroxyurea affects the levels of these proteins. The results were clear. Both ZBTB7A and BCL11A protein levels were reduced by treatment with hydroxyurea. This important result is a first step towards elucidating the molecular mechanism through which hydroxyurea elevates fetal globin expression and an insight into why this small molecule with multiple potential activities can elevate fetal globin gene expression. Hydroxyurea (also known as hydroxycarbamide) is the most widely used treatment for children and adults with sickle cell disease. However, while it is known that treatment with hydroxyurea causes beneficial increases in fetal globin expression, it is not known how hydroxyurea leads to this effect. Two proteins are known to normally keep the expression of fetal globin silent in adult red blood cells. We showed here that hydroxyurea acts to reduce the amounts of these silencing proteins. Lower levels of these proteins could explain how hydroxyurea increases fetal globin expression in people with sickle cell disease and therefore the mechanism by which this drug works.
Funding Information
  • Australian National Health and Medical Research Council to M.C (1164920, 2020861)

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