Hydroxycarbamide alters erythroid gene expression in children with sickle cell anaemia.

Sickle cell anaemia (SCA) is a severe debilitating haematological disorder associated with a high degree of morbidity and mortality. The level of fetal haemoglobin (HbF) is well-recognized as a critical laboratory parameter: lower HbF is associated with a higher risk of vaso-occlusive complications, organ damage, and early death. Hydroxycarbamide treatment can induce HbF, improve laboratory parameters, and ameliorate clinical complications of SCA but its mechanisms of action remain incompletely defined and the HbF response is highly variable.

Epigenetic and molecular profiles of erythroid cells after hydroxyurea treatment in sickle cell anemia.

Hydroxyurea has been shown to be efficacious for the treatment of sickle cell anemia (SCA), primarily through the induction of fetal hemoglobin (HbF). However, the exact mechanisms by which hydroxyurea can induce HbF remain incompletely defined, although direct transcriptional effects and altered cell cycle kinetics have been proposed. In this study, we investigated potential epigenetic and alternative molecular mechanisms of hydroxyurea-mediated HbF induction by examining methylation patterns within the (G)γ-globin promoter and miRNA expression within primary CD71(+) erythrocytes of patients with SCA, both at baseline before beginning hydroxyurea therapy and after reaching maximum tolerated dose (MTD).

Microarray analysis of liver gene expression in iron overloaded patients with sickle cell anemia and beta-thalassemia.

Chronic transfusion therapy is used clinically to supply healthy erythrocytes for patients with sickle cell anemia (SCA) or beta-thalassemia major (TM). Despite the benefits of red blood cell transfusions, chronic transfusions lead to iron accumulation in key tissues such as the heart, liver, and endocrine glands. Transfusion-acquired iron overload is recognized as a cause of morbidity and mortality among patients receiving chronic transfusions.

The roles of alpha IIb beta 3-mediated outside-in signal transduction, thromboxane A2, and adenosine diphosphate in collagen-induced platelet aggregation.

Collagen-induced activation of platelets in suspension leads to alpha(IIb)beta(3)-mediated outside-in signaling, granule release, thromboxane A2 (TxA2) production, and aggregation. Although much is known about collagen-induced platelet signaling, the roles of TxA2 production, adenosine diphosphate (ADP) and dense-granule secretion, and alpha(IIb)beta(3)-mediated outside-in signaling in this process are unclear. Here, we demonstrate that TxA2 and ADP are required for collagen-induced platelet activation in response to a low, but not a high, level of collagen and that alpha(IIb)beta(3)-mediated outside-in signaling is required, at least in part, for this TxA2 production and ADP secretion.

The roles of LAT in platelet signaling induced by collagen, TxA2, or ADP.

The work presented here demonstrates that platelets from mice lacking LAT (linker for the activation of T cells) show reversible aggregation in response to concentrations of collagen that cause TxA2/ADP-dependent irreversible aggregation of control platelets. The aggregation defect of the LAT-deficient platelets was shown to be the result of almost no TxA2 production and significantly diminished ADP secretion. In contrast, the LAT deficiency does not affect aggregation induced by high concentrations of collagen because that aggregation is not dependent on TxA2 and/or ADP.

Role of the Src family kinase Lyn in TxA2 production, adenosine diphosphate secretion, Akt phosphorylation, and irreversible aggregation in platelets stimulated with gamma-thrombin.

Members of the Src family of kinases are abundant in platelets. Although their localization is known, their role(s) in platelet function are not well understood. Lyn is a Src-family kinase that participates in signal transduction pathways elicited by collagen-related peptide; it has also been implicated through biochemical studies in the regulation of von Willebrand factor signaling.