Global gene expression reveals an increase of HMGB1 and APEX1 proteins and their involvement in oxidative stress, apoptosis and inflammation pathways among beta‐thalassaemia intermedia and major phenotypes

Abstract

Summary Beta‐thalassaemia (BT) is classified according to blood transfusion requirement as minor (BTMi), intermedia (BTI) and major (BTM). BTM is the most severe form, requiring regular transfusions while transfusion need is only occasional in BTI. Differential gene expression between patients has not been assessed so far. Here, we evaluated the global gene expression profiles during differentiation of human erythroid cells of two patients carrying the same mutation [CD39, (C → T)], though displaying different phenotypes (BTI and BTM). Considering the role of reactive oxygen species (ROS) in the pathophysiology of thalassaemia, we focused on differentially expressed genes involved in metabolic pathways triggered by ROS, such as inflammation and apoptosis, and, from these, we selected the Apurinic/Apyrimidinic Endodeoxyribonuclease 1 (APEX1) and High Mobility Group Box1 (HMGB1) genes, whose role in BT is not well established. An in‐depth expression analysis of transcriptional and protein levels in patients carrying a range of mutations associated with BT phenotypes indicated that APEX1 was increased in both BTI and BTM. Furthermore, higher amounts of HMGB1 was found in the plasma of BTI patients. Our findings suggest that these proteins have important roles in BT and could represent new targets for further studies aiming to improve the management of the disease.

Human cellular model systems of β-thalassemia enable in-depth analysis of disease phenotype

“…Few pathways involved in oxidative stress have been studied in detail in β-thalassemia erythroid cells 32 , 33 although auto oxidation of α-globin aggregates is hypothesized to lead to increased ROS 34 . Consistent with this, pathways associated with detoxification of ROS were significantly overrepresented (Fig.…”

Acute Promyelocytic Leukemia in a Woman with Thalassemia Intermedia: Case Report and Review of Literature on Hematological Malignancies in β-Thalassemia Patients

“…It is therefore plausible that this peculiar milieu may predispose patients to DS development, especially in pulmonary circulation, particularly susceptible to the thalassemia-induced damage. In fact, β-thalassemia patients display higher levels of markers for endothelial activation such as sICAM-1, sVCAM-1, HMGB1, and P- and E-selectins, reflecting a baseline pro-adhesive phenotype of endothelial cells [ 38 , 39 , 40 ]. Likewise, treatment with ATRA promotes a striking up-regulation of adhesion molecules on APL blast cells such as CD11b, CD11c, CD15, CD65, and CD54, thus leading to lung infiltration and inflammation [ 41 , 42 , 43 ].…”

Human cellular model systems of β-thalassemia enable in-depth analysis of disease phenotype

“…Consistent with this finding, GATA1 levels were significantly decreased in HBB -/basophilic and polychromatic erythroblasts (Supplementary Figure 8). Few pathways involved in oxidative stress have been studied in detail in β-thalassemia erythroid cells 35,36 although auto oxidation of α-globin aggregates is hypothesised to lead to increased ROS 37 . Consistent with this, pathways associated with detoxification of ROS were significantly overrepresented (Fig.…”