bims-conane Biomed News
on Congenital anemias
Issue of 2025–04–13
ten papers selected by
João Conrado Khouri dos Santos, Universidade de São Paulo



  1. World J Clin Cases. 2025 Apr 06. 13(10): 100223
      Beta thalassemia (β-thalassemia) syndromes are a heterogeneous group of inherited hemoglobinopathies caused by molecular defects in the beta-globin gene that lead to the impaired synthesis of beta-globin chains of the hemoglobin. The hallmarks of the disease include ineffective erythropoiesis, chronic hemolytic anemia, and iron overload. Clinical presentation ranges from asymptomatic carriers to severe anemia requiring lifelong blood transfusions with subsequent devastating complications. The management of patients with severe β-thalassemia represents a global health problem, particularly in low-income countries. Until recently, management strategies were limited to regular transfusions and iron chelation therapy, with allogeneic hematopoietic stem cell transplantation available only for a subset of patients. Better understanding of the underlying pathophysiological mechanisms of β-thalassemia syndromes and associated clinical phenotypes has paved the way for novel therapeutic options, including pharmacologic enhancers of effective erythropoiesis and gene therapy.
    Keywords:  Beta thalassemia; Hemoglobin; Hemolysis; Ineffective erythropoiesis; Iron chelation; Molecular defects; Novel therapies; Transfusion
    DOI:  https://doi.org/10.12998/wjcc.v13.i10.100223
  2. Blood Adv. 2025 Apr 08. pii: bloodadvances.2024013695. [Epub ahead of print]
      β-thalassemia is a common monogenic disorder caused by genetic defects in β-globin genes (HBB), resulting in imbalanced synthesis of α-/β-globin and ineffective erythropoiesis. It has been well documented that β-thalassemia patients, or even carriers, mostly experience re-activation of fetal hemoglobin (Hb F), but its underlying mechanisms are incompletely understood. We took advantage of a previously established cohort of 1142 β-thalassemia patients with diverse thalassemic mutations subjected to targeted next-generation sequencing. Genotype-phenotype association studies demonstrated that the HBB: c. -78A>G showed a remarkable effect on the elevation of Hb F levels compared to other β-thalassemic mutations. To experimentally validate the conclusion above, the RNP transfection complex through homology-directed repair (HDR) by electroporation was performed, from which we observed a consistent increase of Hb F expression in both HUDEP-2 and primary CD34+ cell lines. Furthermore, ChIP-qPCR, Dual-luciferase reporter assay, and circular chromosome conformation capture (4C) assays validated a decreased occupancy of the HBB TATA-Box by TBP, leading to boosted expression of γ-globin genes by enhanced interaction between locus control regions (LCRs) and γ-globin gene promoters. The patient-based investigation and experimental validations presented in this study might lead to a better understanding of stage-specific globin-gene expression mediated by competitive binding of distal enhancers (LCRs).
    DOI:  https://doi.org/10.1182/bloodadvances.2024013695
  3. Acta Med Port. 2025 Apr 01. 38(4): 279-280
      
    Keywords:  Anemia; Hyperferritinemia; Iron Overload; Sideroblastic/congenital
    DOI:  https://doi.org/10.20344/amp.22803
  4. Sci Rep. 2025 Apr 07. 15(1): 11843
      X-linked sideroblastic anemia (XLSA) is a hereditary disorder affecting heme biosynthesis, caused by mutations in the ALAS2 gene, which encodes the erythroid-specific enzyme 5-aminolevulinate synthase. This enzyme, which requires pyridoxal 5'-phosphate (PLP) as a cofactor, catalyzes the first and rate-limiting step of heme synthesis in erythroid cells. XLSA is characterized by hypochromic microcytic anemia and ring sideroblasts in bone marrow, with most patients showing variable degrees of response to pyridoxine supplementation; however, female carriers of ALAS2 mutations often present a distinct clinical phenotype. A comprehensive review of the literature reveals over 100 distinct ALAS2 mutations linked to XLSA in more than 240 families. Here, we report seven new patients (four female cases) initially diagnosed with various conditions, later confirmed to have X-linked Sideroblastic Anemia due to ALAS2 mutations through genetic analysis. Among these, five represent novel ALAS2 mutations, including the first ever reported stop-loss mutation in ALAS2 associated with XLSA rather than X-linked dominant protoporphyria (XLDPP). Computational modelling of six reported cases revealed that four mutations significantly impact protein structure, conformation and cofactor interaction, consistent with our enzymatic assays demonstrating reduced ALAS2 activity. Furthermore, X-chromosome studies in female probands revealed a pronounced skewing of X-chromosome, which may provide an explanation for their distinct clinical manifestations in females.
    Keywords:  ALAS2; Congenital sideroblastic anemia; Hereditary anemia; Ring sideroblasts; Stop-loss mutation; X-linked sideroblastic anemia
    DOI:  https://doi.org/10.1038/s41598-025-95590-x
  5. Mol Med. 2025 Apr 08. 31(1): 132
      Despite the established efficacy of hydroxyurea (HU) in increasing fetal hemoglobin (Hb F) levels in patients with intermedia beta-thalassemia (β-thal) and sickle cell anemia, the precise molecular mechanisms underlying these effects remain largely elusive. Understanding these mechanisms is paramount for identifying alternative therapeutic approaches to increase Hb F production while minimizing adverse effects. In this study, we employed weighted gene co-expression network analysis (WGCNA) to investigate the molecular underpinnings of γ-globin switching within GSE90878 dataset. Leveraging this information, we aimed to predict the transcriptome network and elucidate the mechanism of action of HU and Metformin (Met) on this network comprehensively. Through bioinformatic analysis, we identified IGF2BP1 and GCNT2 as key regulators of the γ-globin switching mechanism. To experimentally validate these findings, we utilized the K562 cell line as an erythroid model. Cells were treated with HU (50, 100, and 150 µM) and Met (50, 100, and 150 µM) for 24, 48, and 72 h. The expression levels of the GCNT2, γ-globin, IGF2BP1, miR-199a/b-5p, miR-451-5p and miR-144-3p were quantified using real-time polymerase chain reaction (qPCR). Our results revealed that treatment with HU (150 µM), Met (100 µM), and combination of HU-Met (150/100 µM) significantly increased IGF2BP1 expression by 6.2, 5.3, and 7.1-fold, respectively, after 24 h treatment. Furthermore, treatment with HU (50 µM), Met (50 µM) and HU/Met (50/50 µM) for 24 h led to a 3.3, 1.2, and 5-fold decrease in GCNT2 gene expression, respectively. Notably, the highest levels of γ-globin expression and Hb F production were observed with HU (100 µM), Met (50 µM), and HU/Met (100/50 µM). This study provides compelling evidence that HU and Met significantly enhance γ-globin expression and Hb F production in the K562 cell line. Our findings suggest that these drugs exert their effects by modulating the expression of IGF2BP1 and GCNT2, thus offering valuable insights into potential therapeutic strategies for disorders characterized by low Hb F levels.
    Keywords:   GCNT2 ; IGF2BP1 ; Beta-thalassemia; Hemoglobin F; Hydroxyurea; Metformin
    DOI:  https://doi.org/10.1186/s10020-025-01184-8
  6. Drug Dev Res. 2025 Apr;86(2): e70086
      Sickle cell anemia and beta-thalassemia are the major hemoglobinopathies associated with anemia. Bone marrow transplants or blood transfusion are frequently employed as treatment for these diseases, and erythropoietin analogues are sometimes used to boost erythropoiesis to compensate the destruction of RBCs. RBCs of hemoglobinopathy patients have reduced pyruvate kinase activity and increased oxidative stress, which makes the RBCs prone to destruction and precipitate vaso-occlusive crises and pain. The objective of this study was to evaluate desidustat, a hypoxia inducible factor (HIF) stabilizer in beta thalassemic mice (B6.D2-Hbbd3th/BrkJ) model, phenylhydrazine-induced acute hemolysis in C57 mice model, and sodium metabisulfite-induced sickling in sickle cell disease patient's blood. Desidustat treatment increased hemoglobin, RBCs, and hematocrit in both mice models. Desidustat treatment decreased iron overload, splenomegaly, and oxidative stress in phenylhydrazine-induced hemolytic anemia in mice. Desidustat treatment increased pyruvate kinase activity in RBCs of human, mice, and rats in a dose-dependent manner, and reduced sickling in SCD patients' RBCs. These data indicate that desidustat stimulates pyruvate kinase and attenuates oxidative stress in red blood cells, causes erythrocytosis in thalassemic mice, and reduces sickling in sickle cell patient's blood.
    Keywords:  beta‐thalassemia; desidustat; sickle cell anemia
    DOI:  https://doi.org/10.1002/ddr.70086
  7. Cureus. 2025 Mar;17(3): e80255
       INTRODUCTION: Hemoglobinopathies are genetic disorders characterized by qualitative or quantitative abnormalities in globin chain synthesis. This study focuses on Hemoglobin C (HbC) disease, a structural hemoglobinopathy with diverse clinical and hematological manifestations. HbC disease is particularly relevant in populations with high consanguinity rates, where its phenotypic expression and associated complications warrant further investigation.
    OBJECTIVE: The aim of this study is to describe the hematological profile of patients with HbC disease diagnosed at the Central Hematology Laboratory of Ibn Sina University Hospital over a two-year period.
    MATERIALS AND METHODS: A retrospective, descriptive study was conducted on 37 cases of HbC disease identified between November 2022 and November 2024. The study population included AC heterozygotes, CC homozygotes, SC compound heterozygotes, and HbC/beta-thalassemia combinations. The hematological evaluation comprised complete blood counts, reticulocyte counts, blood smear analysis, and hemoglobin fraction quantification using high-performance liquid chromatography (HPLC).
    RESULTS: The study identified four distinct HbC phenotypes: heterozygous AC (HbAC), homozygous CC (HbCC), compound heterozygous SC (HbSC), and HbC/beta-thalassemia combinations. The SC phenotype was associated with the most severe hematological abnormalities, including significant hemolysis and anemia. Variations in red blood cell morphology and hemoglobin fractions were observed across phenotypes, with elevated fetal hemoglobin (Hb F) levels noted in HbSC patients.
    CONCLUSION: This study highlights the phenotypic diversity of HbC disease in a Moroccan population, emphasizing the role of consanguinity and genetic background in disease expression. The findings underscore the importance of tailored diagnostic and management strategies to address the burden of hemoglobinopathies in high-consanguinity regions.
    Keywords:  anemia; consanguinity; hemoglobin c; hemoglobinopathies; hplc; target cells
    DOI:  https://doi.org/10.7759/cureus.80255
  8. Ann Med. 2025 Dec;57(1): 2490824
       INTRODUCTION: The pathogenesis of anemia and other erythroid dysphasia are mains poorly understood, primarily due to limited knowledge about the differentiation processes and regulatory mechanisms governing erythropoiesis. Erythropoiesis is a highly complex and precise biological process, that can be categorized into three distinct stages: early erythropoiesis, terminal erythroid differentiation, and reticulocyte maturation, and this complex process is tightly controlled by multiple regulatory factors. Emerging evidence highlights the crucial role of epigenetic modifications, particularly histone modifications, in regulating erythropoiesis. Methylation and acetylation are two common modification forms that affect genome accessibility by altering the state of chromatin, thereby regulating gene expression during erythropoiesis.
    DISCUSSION: This review systematically examines the roles of histone methylation and acetylation, along with their respective regulatory enzymes, in regulating the development and differentiation of hematopoietic stem/progenitor cells (HSPCs) and erythroid progenitors. Furthermore, we discuss the involvement of these histone modifications in erythroid-specific developmental processes, including hemoglobin switching, chromatin condensation, and enucleation.Conclusions This review summarizes the current understanding of the role of histone modifications in erythropoiesis based on existing research, as a foundation for further research the mechanisms of epigenetic regulatory in erythropoiesis.
    Keywords:  Erythropoiesis; early hematopoiesis; gene regulation; histone acetylation; histone methylation
    DOI:  https://doi.org/10.1080/07853890.2025.2490824
  9. bioRxiv. 2025 Mar 25. pii: 2025.03.24.645036. [Epub ahead of print]
      Increasing fetal-type hemoglobin (HbF) expression in adult erythroid cells holds promise in the treatment of sickle cell disease (SCD) and β-thalassemia. We have identified MLL1 complex as a critical regulator of fetal and embryonic hemoglobin repression. Knockdowns of MEN1 and KMT2A, encoding essential components of the complex, caused a significant downregulation of BCL11A expression and a substantial increase in γ- and ε-globin mRNA levels in HUDEP-2 cells. Significant binding of MEN1 and KMT2A were readily detected at the promoter and a critical enhancer of BCL11A in HUDEP-2 cells, suggesting that BCL11A is a direct transcriptional target of MLL1 complex. Consistent with these results, MEN1 or KMT2A knockdown in normal human CD34 + hematopoietic stem and progenitor cells (HSPCs) induced to undergo erythroid differentiation also significantly decreased their BCL11A expression and increased their γ- and ε-globin expression and the production of F cells in the culture. Treatment of these cells with MENIN inhibitors yielded similar results and promoted erythroid differentiation with minimal effects on their growth. These findings underscore a critical role of MLL1 complex in regulating fetal and embryonic hemoglobin expression and suggest that MENIN inhibitors could offer a promising therapeutic approach for sickle cell disease and β-thalassemia.
    DOI:  https://doi.org/10.1101/2025.03.24.645036