Abstract
The molecular mechanisms governing γ-globin expression in a subset of fetal hemoglobin (α2γ2: HbF) expressing red blood cells (F-cells) and the mechanisms underlying the variability of response to hydroxyurea induced γ-globin expression in the treatment of sickle cell disease are not completely understood. Here we analyzed intra-person clonal populations of basophilic erythroblasts (baso-Es) derived from bone marrow common myeloid progenitors in serum free cultures and report the level of fetal hemoglobin production in F-cells negatively correlates with expression of BCL11A, KLF1 and TAL1. We then examined the effects of hydroxyurea on these three transcription factors and conclude that a successful induction of γ-globin includes a reduction in BCL11A, KLF1 and TAL1 expression. These data suggests that expression changes in this transcription factor network modulate γ-globin expression in F-cells during steady state erythropoiesis and after induction with hydroxyurea.
Highlights
Understanding the mechanisms which govern γ-globin expression in adult erythropoiesis is important for developing therapeutic targets for the β-hemoglobinopathies [1]
Using an approach based on the analysis of clonal populations of basophilic erythroblasts derived in serum free culture of bone marrow (BM) common myeloid progenitors (CMP), we report here that the level of HbF production in baso-Es is not yet determined at the CMP level since sub-cultures of daughter cells derived from the same CMPs exhibit different levels of γ-globin expression
We show that the variations in HbF levels in normal basophilic erythroblasts negatively correlates with expression of BCL11A, KLF1 and TAL1 and that the same genes are further down-regulated after successful induction with HU
Summary
Understanding the mechanisms which govern γ-globin expression in adult erythropoiesis is important for developing therapeutic targets for the β-hemoglobinopathies [1]. Induction of γ-globin expression decreases the formation of sickle polymers in red blood cells under de-oxygenation conditions. An increase in fetal hemoglobin (α2γ2: HbF) to a threshold level of 20% has been associated with a more benign disease course [2, 3]. Hydroxyurea (HU) was the first drug approved by the FDA for clinical use in sickle cell patients to induce HbF [4] after its clinical effectiveness in reducing acute disease complications of painful crises and hospitalizations was demonstrated [5, 6]. The ameliorative effects of HU on sickle cell disease include improved blood flow in the microcirculation and a decreased.
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