Hemoglobin switching is a complex biological process not yet fully elucidated. The mechanism regulating the suppression of fetal hemoglobin (HbF) expression is of particular interest because of the positive impact of HbF on the course of diseases such as β-thalassemia and sickle cell disease, hereditary hemoglobin disorders that affect the health of countless individuals worldwide. Several transcription factors have been implicated in the control of HbF, of which BCL11A has emerged as a major player in HbF silencing.
View Article and Find Full Text PDFβ-Thalassemias are inherited anemias that are caused by the absent or insufficient production of the β chain of hemoglobin. Here we report 6-8-year follow-up of four adult patients with transfusion-dependent β-thalassemia who were infused with autologous CD34 cells transduced with the TNS9.3.
View Article and Find Full Text PDFHereditary persistence of fetal haemoglobin (HPFH) is the major modifier of the clinical severity of β-thalassaemia. The homozygous mutation c.-196 C>T in the Aγ-globin (HBG1) promoter, which causes Sardinian δβ -thalassaemia, is able to completely rescue the β-major thalassaemia phenotype caused by the β 39-thalassaemia mutation, ensuring high levels of fetal haemoglobin synthesis during adulthood.
View Article and Find Full Text PDFThe human fetal γ-globin gene is repressed in the adult stage through complex regulatory mechanisms involving transcription factors and epigenetic modifiers. Reversing γ-globin repression, or maintaining its expression by manipulating regulatory mechanisms, has become a major clinical goal in the treatment of β-hemoglobinopathies. Here, we identify the orphan nuclear receptor Coup-TFII (NR2F2/ARP-1) as an embryonic/fetal stage activator of γ-globin expression.
View Article and Find Full Text PDFPurpose: The aim of this study has been to evaluate the physical, psychological, and social well-being in a large group of Sardinian adult patients with transfusion-dependent beta-Thalassemia when compared with a group of healthy subjects of the same age and geographical extraction.
Methods: Male or female patients ≥ 18 years of age with Thalassemia major on regular transfusion at Thalassemia Center in Cagliari (Italy) were requested to complete the World Health Organization Quality of life-BREF (WHOQOL-BREF) questionnaire. The WHOQOL-BREF was also made available online to age- and sex-matched non-thalassemic adult subjects living in Sardinia.
Limited information is available on the hematological characterization of the α-thalassemia carrier in pediatric age. The objective of this report was to evaluate the red cell indices according to the α-globin genotype in a cohort of children evaluated in Sardinia. Moreover, we verified the frequency of different α-globin genotypes in this cohort.
View Article and Find Full Text PDFAllogeneic hematopoietic stem cell transplantation (HSCT) in thalassemia remains a challenge. We reported a single-centre case-control study of a large cohort of 516 children and adult patients treated with HSCT or blood transfusion support and iron chelation therapy; 258 patients (median age 12, range 1-45) underwent sibling (67%) or unrelated (33%) HSCT; 97 patients were adults (age ≥ 16 years). The median follow-up after HSCT was 11 years (range 1-30).
View Article and Find Full Text PDFα-thalassemia carriers are common in Mediterranean regions, particularly in the Sardinian population. Their haematological phenotype is characterized by reduced MCV and/or MCH with normal or slightly reduced HbA2 levels and normal HbF. Krüppel-like factor 1 (KLF1) is a pleiotropic erythroid transcription factor that is essential for haematopoiesis.
View Article and Find Full Text PDFBackground: Cellular biobanking is a key resource for collaborative networks planning to use same cells in studies aimed at solving a variety of biological and biomedical issues. This approach is of great importance in studies on β-thalassemia, since the recruitment of patients and collection of specimens can represent a crucial and often limiting factor in the experimental planning.
Methods: Erythroid precursor cells were obtained from 72 patients, mostly β-thalassemic, expanded and cryopreserved.
The identification of drugs capable of reactivating γ-globin to ameliorate β-thalassemia and Sickle Cell anemia is still a challenge, as available γ-globin inducers still have limited clinical indications. High-throughput screenings (HTS) aimed to identify new potentially therapeutic drugs require suitable first-step-screening methods combining the possibility to detect variation in the γ/β globin ratio with the robustness of a cell line. We took advantage of a K562 cell line variant expressing β-globin (β-K562) to set up a new multiplexed high-content immunofluorescence assay for the quantification of γ- and β-globin content at single-cell level.
View Article and Find Full Text PDFWe report genome-wide association study results for the levels of A1, A2 and fetal hemoglobins, analyzed for the first time concurrently. Integrating high-density array genotyping and whole-genome sequencing in a large general population cohort from Sardinia, we detected 23 associations at 10 loci. Five signals are due to variants at previously undetected loci: MPHOSPH9, PLTP-PCIF1, ZFPM1 (FOG1), NFIX and CCND3.
View Article and Find Full Text PDFNephrol Dial Transplant
July 2015
Background: Pregnancy on dialysis is increasingly being reported. This study evaluates the behavioural profile of the children of mothers on dialysis and the parental stress their mothers undergo when compared with a group of mothers affected by a different chronic disease (microcythaemia) and a group of healthy control mothers.
Methods: Between 2000 and 2012, 23 on-dialysis mothers gave birth to 24 live-born children in Italy (23 pregnancies, 1 twin pregnancy, one of the twins deceased soon after delivery); of these, 16 mothers and 1 father (whose wife died before the inquiry) were included in the study (1 mother had died and the father was unavailable; 2 were not asked to participate because their children had died and 3 were unavailable; children: median age: 8.
The aim of the study was to assess the current state in terms of liver and heart iron overload as well as of liver and heart related morbidity and mortality in a large cohort of thalassemia patients. Myocardial iron loading was present in 28.9% patients, which was severe in 3.
View Article and Find Full Text PDFClinical and hematologic characteristics of beta(β)-thalassemia are determined by several factors resulting in a wide spectrum of severity. Phenotype modulators are: HBB mutations, HBA defects and fetal hemoglobin production modulators (HBG2:g.-158C>T polymorphism, HBS1L-MYB intergenic region and the BCL11A).
View Article and Find Full Text PDFβ-thalassemia and sickle cell disease are widespread fatal genetic diseases. None of the existing clinical treatments provides a solution for all patients. Two main strategies for treatment are currently being investigated: (i) gene transfer of a normal β-globin gene; (ii) reactivation of the endogenous γ-globin gene.
View Article and Find Full Text PDFIncreased hemoglobin A(2) (HbA(2); ie, levels > 3.9%) is the most important feature of β-thalassemia carriers. However, it is not uncommon to find persons with borderline HbA(2) (levels, 3.
View Article and Find Full Text PDFA key regulatory gene in definitive erythropoiesis is the erythroid Kruppel-like factor (Eklf or Klf1). Klf1 knockout (KO) mice die in utero due to severe anemia, while residual circulating red blood cells retain their nuclei. Dnase2a is another critical gene in definitive erythropoiesis.
View Article and Find Full Text PDFβ-thalassemias are heterogeneous hereditary anemias characterized by a reduced output of β-globin chains. The disease is most frequent in the temperate regions of the world, where it represents an important health problem. In the last decades, several programs, aimed at controlling the birth rate of thalassemia newborns by screening and prenatal diagnosis of populations with high risk of β-thalassemia, have been successful accomplished.
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