bims-conane Biomed News
on Congenital anemias
Issue of 2025–03–23
thirteen papers selected by
João Conrado Khouri dos Santos, Universidade de São Paulo
  1. In vivo deletion of a GWAS-identified Myb distal enhancer acts on Myb expression, globin switching, and clinical erythroid parameters in β-thalassemia.
  2. EXPRESS: Research on Iron Regulatory Erythroid Factors in Children with β-Thalassemia.
  3. Evaluation of haemoglobin constant spring phenotypes and their haematological characteristics among high school students in Terengganu, Malaysia: A single - centred study.
  4. Impact of HLA Alloimmunization in Gene-Modified Autologous Stem Cell Transplant For Transfusion-Dependent Thalassemia.
  5. Creating New Cis-Regulatory Elements of HBD to Reactivate Delta-Globin.
  6. Alpha Thalassemia Major: From a Lethal to a Treatable Condition.
  7. Beyond blood transfusions: exploring iron chelation therapies in transfusion-dependent beta-thalassemia.
  8. RepID depletion enhances TWS119-induced erythropoiesis through chromatin reprogramming and transcription factor recruitment.
  9. αß T-cell depleted haploidentical stem cell transplantation for pediatric and young adult patients with transfusion-dependent thalassemia.
  10. Balancing benefits and burdens: a systematic review on ethical and social dimensions of gene and cell therapies for hereditary blood diseases.
  11. Hematological indicators and their impact on maternal and neonatal outcomes in pregnancies with thalassemia traits.
  12. Infantile Pure Red Cell Aplasia Secondary to Deficiency of Adenosine Deaminase2 (DADA2) Syndrome-Time to Think Beyond Diamond Blackfan Anemia.
  13. Hepcidin deletion disrupts iron homeostasis and hematopoiesis in zebrafish embryogenesis.
  1. Sci Rep. 2025 Mar 15. 15(1): 8996
    In vivo deletion of a GWAS-identified Myb distal enhancer acts on Myb expression, globin switching, and clinical erythroid parameters in β-thalassemia.
    Virginie Deleuze, Tharshana Stephen, Mohammad Salma, Cédric Orfeo, Ruud Jorna, Alex Maas, Vilma Barroca, Marie-Laure Arcangeli, Charles-Henri Lecellier, Charlotte Andrieu-Soler, Frank Grosveld, Eric Soler.
      Genome-wide association studies (GWAS) have identified numerous genetic variants linked to human diseases, mostly located in non-coding regions of the genome, particularly in putative enhancers. However, functional assessment of the non-coding GWAS variants has progressed at slow pace, since the functions of the vast majority of genomic enhancers have not been defined, impeding interpretation of disease-susceptibility variants. The HBS1L-MYB intergenic region harbors multiple SNPs associated with clinical erythroid parameters, including fetal hemoglobin levels, a feature impacting disease severity of beta-hemoglobinopathies such as sickle cell anemia and beta-thalassemia. HBS1L-MYB variants cluster in the vicinity of several MYB enhancers, altering MYB expression and globin switching. We and others have highlighted the conserved human MYB - 84kb enhancer, known as the - 81kb enhancer in the mouse, as likely candidate linked to these traits. We report here the generation of a Myb - 81kb enhancer knock-out mouse model, and shed light for the first time on its impact on steady state erythropoiesis and in beta-thalassemia in vivo.
    Keywords:  Enhancer; Erythropoiesis; Globin switching; MYB; Mouse KO; Thalassemia
    DOI:  https://doi.org/10.1038/s41598-025-94222-8
  2. J Investig Med. 2025 Mar 18. 10815589251331618
    EXPRESS: Research on Iron Regulatory Erythroid Factors in Children with β-Thalassemia.
    Yaxuan Cao, Ken Huang, Jianming Luo.
      To investigate the differences in relative mRNA expression levels of the novel iron regulatory erythroid factors FAM210B, CCDC115, HO-1, PCBP1, PCBP2, NCOA4, and Nrf2 in children with β-thalassemia major (β-TM) before and after transfusion therapy. A total of 98 children with transfusion-dependent β-thalassemia were recruited from the First Affiliated Hospital of Guangxi Medical University between October 2022 and May 2023. The children were classified based on their hemoglobin (Hb) levels: 57 cases with Hb ≤ 90 g/L and 41 cases with Hb > 90 g/L. Real-time fluorescence quantitative PCR was employed to assess the relative mRNA expression between the groups. The mRNA expression levels of FAM210B, HO-1, and NCOA4 were significantly higher in the Hb ≤ 90 g/L group compared to the Hb > 90 g/L group (P < 0.05). Moreover, higher relative expression levels of FAM210B and NCOA4 correlated with an increased likelihood of requiring blood transfusions in β-TM children. The differences in the remaining factors did not reach statistical significance. FAM210B and NCOA4 may serve as indicators of erythropoiesis and the degree of anemia in children with β-TM. Further research is warranted to explore their potential as therapeutic targets for β-thalassemia and other erythropoietic disorders.
    Keywords:  Anemia; Hematologic Diseases; Hemoglobins
    DOI:  https://doi.org/10.1177/10815589251331618
  3. Saudi Med J. 2025 Mar;46(3): 292-298
    Evaluation of haemoglobin constant spring phenotypes and their haematological characteristics among high school students in Terengganu, Malaysia: A single - centred study.
    Sharifatul F Embong, Sumaiyah Adzahar, Adibah Daud, Mohammad H Nordin, Sarah A Halim, Wan Zuhairah W Embong, Nabilah Rameli, Razan H Zulkeflee, Rosnah Bahar.
       OBJECTIVES: To assess the prevalence of hemoglobin constant spring (Hb CS) in the Terengganu population, to evaluate the haematological parameters of individuals with heterozygous Hb CS, homozygous Hb CS, and compound heterozygous Hb CS, and to compare the effectiveness of high-performance liquid chromatography (HPLC) and capillary electrophoresis (CE) in detecting Hb CS.
    METHODS: This study employed a cross-sectional design involving Form 4 secondary school students from Terengganu. Hemoglobin variants were analyzed using CE (CAPILLARYS2 Flex-Piercing System) and HPLC (VARIANT II). Molecular testing, including multiplex polymerase chain reaction (PCR) and amplification refractory mutation system-PCR techniques, was carried out to detect alpha thalassemia mutations.
    RESULTS: The prevalence of Hb CS revealed 92.2% heterozygous (mean zone 2 CE peak value of 0.7%), 7.2% compound heterozygous (mean zone 2 CE peak value of 1.2%), and 0.5% homozygous cases (mean zone 2 CE peak value of 4.5%).
    CONCLUSION: The study highlights a significant prevalence of Hb CS among the Terengganu population, with heterozygous cases being the most common. The peak values in zone 2 CE varied significantly among the heterozygous, compound heterozygous, and homozygous HbCS cases, indicating the potential utility of these measurements in distinguishing between different clinical phenotypes.
    Keywords:  alpha thalassemia; capillary electrophoresis; haemoglobin constant spring; high performance liquid chromatography
    DOI:  https://doi.org/10.15537/smj.2025.46.3.20240771
  4. Blood. 2025 Mar 16. pii: blood.2024027034. [Epub ahead of print]
    Impact of HLA Alloimmunization in Gene-Modified Autologous Stem Cell Transplant For Transfusion-Dependent Thalassemia.
    Nora M Gibson, Eugene Khandros, Caitlin W Elgarten, Elizabeth Worster, Dimitrios S Monos, Alexis A Thompson, Janet L Kwiatkowski, Timothy Olson.
      We report our single center experience demonstrating that HLA Class I alloimmunization predicts longer time to platelet engraftment, increased bleeding complications and higher transfusion requirements in patients undergoing gene-modified hematopoietic stem cell transplant for transfusion-dependent beta thalassemia.
    DOI:  https://doi.org/10.1182/blood.2024027034
  5. Hum Gene Ther. 2025 Mar 21.
    Creating New Cis-Regulatory Elements of HBD to Reactivate Delta-Globin.
    Lini Chen, Diandian Liu, Weicong Hong, Luhong Xu, Lin Cheng, Ying Luo, Hui Xu, Junbin Liang, Jianpei Fang, Xinyu Li.
      β-thalassemia and sickle cell disease (SCD) are global monogenic blood system disorders, and reactivated δ-globin is expected to replace missing or abnormal β-globin. With the development of gene editing technology, activating γ-globin for treating β-thalassemia and SCD has been highly successful. However, δ-globin, as another important potential therapeutic target, has few related studies. Gene editing technology introduced cis-acting elements, including NF-Y, KLF1, GATA1, and TAL1, into the regulatory region of HBD, successfully activating the expression of δ-globin. It was confirmed that the activation effect of δ-globin was closely related to the location of the introduced cis-acting elements. In this study, the mutation creates a de novo binding site for KLF1 at -85∼93 bp upstream of the transcription start site of the HBD gene, as well as the site for TAL1 and GATA1 cobinding motifs at -59 to ∼-78 bp, which could effectively activate δ-globin.
    Keywords:  GATA1; KLF1; TAL1; genome editing; β-thalassemia; δ-globin
    DOI:  https://doi.org/10.1089/hum.2024.186
  6. Hemoglobin. 2025 Jan;49(1): 1-2
    Alpha Thalassemia Major: From a Lethal to a Treatable Condition.
    Cornelis Harteveld.
      
    DOI:  https://doi.org/10.1080/03630269.2025.2476243
  7. Ann Med Surg (Lond). 2025 Jan;87(1): 13-17
    Beyond blood transfusions: exploring iron chelation therapies in transfusion-dependent beta-thalassemia.
    Muhammad Talha, Mohammad Haris Ali, Sonia Hurjkaliani, Zainab Syyeda Rahmat, Haleema Sadia, Md Al Hasibuzzaman, Ahsan Ul Qayyum Uzair.
       Introduction: Abnormal hemoglobin, or hemoglobinopathy, affects about 7% of the global population. Major hemoglobinopathies like beta-thalassemia and sickle cell disease require regular blood transfusions, leading to chronic iron overload. This review examines the efficacy and safety of deferiprone, an oral iron chelator, in managing iron overload in pediatric patients with transfusion-dependent conditions.
    Methods: Data were sourced from PubMed, Google Scholar, and relevant articles, focusing on randomized controlled trials (RCTs) published between 2010 and 2023. The search terms included "deferiprone," "iron chelation," "transfusion," "iron overload," "hemoglobinopathies," and "thalassemia." Three RCTs met the inclusion criteria, involving 521 pediatric patients.
    Results: The START trial demonstrated that early-start deferiprone significantly reduced iron load compared to placebo, with no severe adverse events. The DEEP-2 study found deferiprone non-inferior to deferasirox in terms of efficacy and safety. Another trial highlighted the benefits of early deferiprone therapy in delaying iron overload symptoms without serious side effects. Common adverse effects included pyrexia, nasopharyngitis, and decreased neutrophil count, but no significant differences in growth parameters, creatinine, or prolactin levels were observed.
    Conclusion: Deferiprone shows significant promise in managing iron overload in pediatric patients, with comparable effectiveness to existing therapies and a favorable safety profile. Its oral administration is advantageous for young children. However, long-term studies are needed to fully understand its safety and efficacy. Addressing challenges such as patient compliance and adverse effects through education, personalized medicine, and advanced monitoring techniques can further improve treatment outcomes for beta-thalassemia patients.
    Keywords:  FDA-approved; children; deferiprone; infants; transfusion-induced beta-thalassemia (TBT)
    DOI:  https://doi.org/10.1097/MS9.0000000000002796
  8. Genes Genomics. 2025 Mar 18.
    RepID depletion enhances TWS119-induced erythropoiesis through chromatin reprogramming and transcription factor recruitment.
    Seon-Mi Ok, Jae-Hyun Jo, Hyo Je Cho, Sang-Min Jang.
       BACKGROUND: Erythrocytes, derived from hematopoietic stem cells, are essential for oxygen transport, ensuring survival in all vertebrate animals. The process of erythropoiesis is associated with gene expression changes, but many key regulatory factors that govern erythroid differentiation remain to be fully understood.
    OBJECTIVE: This study investigates the role of TWS119, a known GSK3β inhibitor, in inducing erythropoiesis in K562 erythroleukemia cells and explores the impact of Replication initiation determinant protein (RepID) depletion on the process.
    METHODS: K562 cells were treated with TWS119 and erythropoiesis markers including various erythrocytic phenotypes were assessed. Chromatin-immunoprecipitation analysis was employed to examine the changes in chromatin structure and gene expression regulation. The impact of RepID depletion on TWS119-induced erythropoiesis was also evaluated by analyzing globin promoter euchromatinization and NRF2 binding.
    RESULTS: TWS119 treatment led to erythrocytic phenotypes in K562 cells, such as red pellet formation, enucleation, and nucleus condensation, along with the upregulation of erythropoiesis markers. Furthermore, RepID depletion accelerated TWS119-mediated erythropoiesis. Chromatin-immunoprecipitation analysis revealed euchromatinization of the globin promoter and enhanced NRF2 binding in RepID-depleted cells, suggesting a mechanism of gene expression regulation during erythropoiesis.
    CONCLUSION: This study demonstrates that TWS119 can induce erythropoiesis in K562 cells, and that RepID depletion enhances this process by modulating chromatin structure and facilitating transcription factor binding. These findings highlight a RepID-dependent mechanism in the regulation of gene expression during erythropoiesis.
    Keywords:  Erythropoiesis; Euchromatin; Globin; RepID; TWS119
    DOI:  https://doi.org/10.1007/s13258-025-01627-w
  9. Bone Marrow Transplant. 2025 Mar 18.
    αß T-cell depleted haploidentical stem cell transplantation for pediatric and young adult patients with transfusion-dependent thalassemia.
    Katharina Kleinschmidt, Gina Penkivech, Anja Troeger, Juergen Foell, Tarek Hanafee-Alali, Stefanie Leszczak, Marcus Jakob, Sonja Kramer, Silke Kietz, Petra Hoffmann, Claudia Behrendt-Böhm, Carina Kaess, Andreas Brosig, Robert Offner, Daniel Wolff, Selim Corbacioglu.
      Life expectancy of patients with severe transfusion-dependent beta-thalassemia (TDT) remains below that of the general population. Allogenic hematopoietic stem cell transplantation (HSCT) is the standard curative treatment. Due to the paucity of matched donor (MD) availability, haploidentical HSCT (haplo-HSCT) is a reasonable alternative. Twenty patients with TDT (median age 10 years; range 2-23) received either a matched sibling donor (MSD; n = 7) or a haplo-HSCT (n = 13) in a single center (Regensburg, Germany) between 2016 and 2022, including two patients referred for a haplo-HSCT as rescue failing prior MD- and haplo-HSCT, respectively. The conditioning regimen consisted of anti-thymocyte globulin (ATG; Grafalon®), treosulfan, thiotepa, and fludarabine (FTT). Immunosuppression consisted of a calcineurin inhibitor and mycophenolate mofetil (MMF). At a median follow-up of 37 months (range 6-90), overall survival (OS) was 100% with a disease-free survival (DFS) of 100% in MSD and 92% in haplo-HSCT, respectively. Two patients in haplo-HSCT experienced graft failure, one achieving DFS after a second haplo-HSCT. No acute graft-versus-host disease (aGvHD) ≥ °III or severe chronic GvHD (cGvHD) were observed. No sinusoidal obstruction syndrome (SOS) was observed in this high-risk population. Treosulfan-based T-cell depleted haplo-HSCT can achieve comparable OS and DFS even in young adult TDT patients with no SOS/VOD.
    DOI:  https://doi.org/10.1038/s41409-025-02546-w
  10. BMC Med Ethics. 2025 Mar 14. 26(1): 36
    Balancing benefits and burdens: a systematic review on ethical and social dimensions of gene and cell therapies for hereditary blood diseases.
    L C van Hooff, E-M Merz, A S Kidane Gebremeskel, J A de Jong, G L Burchell, J E Lunshof.
       BACKGROUND: Sickle cell disease (SCD) and Diamond-Blackfan anemia syndrome (DBAS) are two hereditary blood diseases that present significant challenges to patients, their caregivers, and the healthcare system. Both conditions cause severe health complications and have limited treatment options, leaving many individuals without access to curative therapies like hematopoietic stem cell transplantation. Recent advancements in gene and cell therapies offer the potential for a new curative option, marking a pivotal shift in the management of these debilitating diseases. However, the implementation of these therapies necessitates a nuanced understanding of the ethical and social implications.
    METHODS: In this mixed methods systematic review, we explore the responsible development and implementation of gene and cell therapies for SCD and DBAS and aim to sketch a path toward ethically and socially sound implementation. Drawing upon principles of Responsible Research & Innovation and the 4A framework of availability, accessibility, acceptability, and affordability, we thematically analyze existing research to illuminate the ethical and social dimensions of these therapies. Following established PRISMA and JBI Manual guidelines, a search across multiple databases yielded 51 peer-reviewed studies with publication dates ranging from 1991 to 2023.
    RESULTS: Our thematic analysis shows that the theme of acceptability is heavily shaped by interactions between patients, caregivers, healthcare professionals and researchers, influencing treatment decisions and shaping the development of curative gene and cell therapies. Despite the generally positive perspective on these therapies, factors like the limited treatment options, financial constraints, healthcare professional attitudes, and (historical) mistrust can impede stakeholder decision-making. While acceptability focuses on individual decisions, the themes of availability, accessibility, and affordability are interconnected and primarily driven by healthcare systems, where high research and development costs, commercialization and a lack of transparency challenge equitable access to these therapies. This diminishes the acceptability for patients, revealing a complex interdependence of the themes.
    CONCLUSIONS: The findings suggest the need for improved communication strategies in clinical practice to facilitate informed decision-making for patients and caregivers. Policy development should focus on addressing pricing disparities and promoting international collaboration to ensure equitable access to therapies. This review has been pre-registered in PROSPERO under registration number CRD42023474305.
    Keywords:  Acceptability; Accessibility; Affordability; Anemia; Availability; Cell and gene therapies; Diamond-Blackfan anemia syndrome; Hereditary blood disease; Responsible research and innovation; Sickle cell disease
    DOI:  https://doi.org/10.1186/s12910-025-01188-3
  11. J Perinat Med. 2025 Mar 17.
    Hematological indicators and their impact on maternal and neonatal outcomes in pregnancies with thalassemia traits.
    Ratana Meng, Hai-Ning Bi, Chanrith Mork, Ji-Fang Shi.
       OBJECTIVES: The aim of this study is to compare the obstetric, neonatal, and hematological indicators of pregnant women with thalassemia traits with those of pregnant women without such traits.
    METHODS: This retrospective cohort study was conducted from January 2017 to October 2023 at the Department of Obstetrics and Gynecology, The First Affiliated Hospital of Dali University. The study included 185 cases of thalassemia traits and 185 control cases. Data were analysis using the SPSS program (Version 27.0).
    RESULTS: Significant differences were observed in gravidity and parity histories (p<0.05). Significant differences were also observed in the rates of gestational diabetes mellitus (GDM), hypertensive disorder of pregnancy (HDP), cesarean delivery, adherent placenta, and anemia in the second and third trimesters following the number of RR (95 % CI): 2.182 (1.101-4.324), 9.000 (1.152-70.325), 2.091 (1.555-2.811), 3.401 (1.280-9.009), 4.222 (2.102-8.481), and 2.053 (1.476-2.855), respectively (p<0.05). However, no significant differences were noted in the rates of preterm birth, low birth weight, macrosomia, intrauterine growth restriction, fetal distress, fetal malformation, and stillbirth (p>0.05). Furthermore, significant differences were noted in the levels of hemoglobin (Hb), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and red cell distribution width (RDW) during the first, second, and third trimesters (p<0.05).
    CONCLUSIONS: As pregnancy progresses, the levels of Hb tend to decrease, while the MCH and RDW levels increase. On the other hand, the level of MCV remain the same overtime. Thalassemia traits are significantly associated with anemia during pregnancy, particularly in the second and third trimesters. Furthermore, thalassemia traits are related to an increased incidence of GDM, HDP, and cesarean delivery.
    Keywords:  hematological indicators; neonatal outcomes; obstetric outcomes; pregnancy complications; thalassemia
    DOI:  https://doi.org/10.1515/jpm-2024-0394
  12. Pediatr Blood Cancer. 2025 Mar 17. e31656
    Infantile Pure Red Cell Aplasia Secondary to Deficiency of Adenosine Deaminase2 (DADA2) Syndrome-Time to Think Beyond Diamond Blackfan Anemia.
    Amiya Ranjan Nayak, Jasmita Dass, Himil Parikh, Swapnil Tripathi, Pratyusha Gudapati, Renjith Verghese, Richa Chauhan, Ganesh Kumar Viswanathan, Pradeep Kumar, Rishi Dhawan, Tulika Seth, Manoranjan Mahapatra, Narendra Kumar Bagri, Mukul Aggarwal.
      Deficiency of adenosine deaminase 2 (DADA2) is a rare autosomal recessive disorder characterized by vasculopathy, immunodeficiency, and hematological abnormalities. Its presentation as infantile pure red cell aplasia (PRCA) often mimics Diamond Blackfan anemia (DBA), leading to diagnostic delays and suboptimal management. This study retrospectively analyzed nine cases of DADA2-related PRCA diagnosed over 5 years at a tertiary care hospital. All patients harbored homozygous ADA2 mutations, predominantly p.Ile93Thr, and presented with severe anemia and reticulocytopenia. Misdiagnosed initially as DBA, none responded to steroid therapy. Our findings emphasize the need for comprehensive genetic analysis in PRCA to distinguish DADA2 from DBA for appropriate treatment.
    Keywords:  DADA2; Diamond Blackfan anemia; autoinflammatory vasculopathy; pure red cell aplasia
    DOI:  https://doi.org/10.1002/pbc.31656
  13. Development. 2025 Mar 20. pii: dev.204307. [Epub ahead of print]
    Hepcidin deletion disrupts iron homeostasis and hematopoiesis in zebrafish embryogenesis.
    Wenyi Yang, Mingjian Peng, Youquan Wang, Xiaowen Zhang, Wei Li, Xue Zhai, Zhichao Wu, Peng Hu, Liangbiao Chen.
      Iron is essential for cell growth and hematopoiesis, regulated by hepcidin (hamp). However, hamp's role in zebrafish hematopoiesis remains unclear. Here, we created a stable hamp knockout zebrafish model using Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR-associated nuclease 9 system (CRISPR/Cas9 system). Our study revealed that hamp deletion led to maternal iron overload in embryos, significantly downregulating hemoglobin genes and reducing hemoglobin content. Single-cell RNA sequencing identified abnormal expression patterns in blood progenitor cells, with a specific progenitor subtype showing increased ferroptosis and delayed development. By crossing hamp knockout zebrafish with a gata1+ line (blood cells labeled fish line), we confirmed ferroptosis in blood progenitor cells. These findings underscore hamp's critical role in iron regulation and hematopoiesis, offering novel insights into developmental biology and potential therapeutic targets for blood disorders.
    Keywords:   hamp ; Hematopoiesis; Single cell transcriptomics; Zebrafish
    DOI:  https://doi.org/10.1242/dev.204307
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