bims-conane Biomed News
on Congenital anemias
Issue of 2026–01–04
ten papers selected by
João Conrado Khouri dos Santos, Universidade de São Paulo
  1. Identification of RBM3 as a novel regulator of human fetal hemoglobin expression.
  2. Management of transfusion-dependent β-thalassaemia in the era of novel therapies: a prioritisation-based matrix for settings with limited resources.
  3. The diagnosis and treatment of red cell membrane disorders: algorithm for the general hematologist.
  4. Molecular dynamics insights into novel and nano-rare de novo mutations in the ribosomal proteins S19 and L26 causing Diamond-Blackfan anemia in Iranian patients.
  5. Is occlusive retinal vascular disease linked to hereditary spherocytosis postsplenectomy? A case series.
  6. Global comprehensive transcriptomic and proteomic analyses of murine terminal erythroid differentiation.
  7. Pregnancy Outcomes in Women With Thalassemia Trait: A Multicenter Cohort Study.
  8. Crossed Erythrocytes Agglutination Pattern Observed in a Patient With Hereditary Elliptocytosis.
  9. Thalassaemia clinical trials in war-stricken Lebanon: a story of struggle and resilience.
  10. Thalassaemia: advocacy, resilience, and adaptability.
  1. Int Immunopharmacol. 2025 Dec 26. pii: S1567-5769(25)02096-X. [Epub ahead of print]170 116107
    Identification of RBM3 as a novel regulator of human fetal hemoglobin expression.
    Shuangping Ma, Xianting Liu, Yiran Qin, Yilong Wang, Yu Feng, Binfeng Cheng, Lei Wang.
      Sickle cell disease (SCD) and β-thalassemia are autosomal recessive genetic disorders caused by abnormal synthesis of β-globin chains. Reversing the transition of fetal-to-adult hemoglobin after birth shows great potential in the treatment of these disorders. Here, we identified an RNA-binding protein, RBM3, as a novel HbF (HbF, α2γ2) suppressor. Specifically, downregulation of RBM3 in the erythroid progenitor cell line HUDEP-2 robustly induced γ-globin expression at both the mRNA and protein levels, with a slight impact on β-globin levels. Conversely, overexpression of RBM3 in HUDEP-2 cells led to a marked reduction in γ-globin expression. According to the previous study, we introduced specific inhibitors targeting FAK and Src to block RBM3 protein synthesis. Surprisingly, treatment with the FAK inhibitor resulted in a significant increase in γ-globin expression, whereas the Src inhibitor had little effect. Mechanistically, RBM3 depletion accelerated the degradation of BCL11A protein at the post-transcriptional level, without affecting its mRNA stability. Moreover, RBM3 silencing restricted the overall translation efficiency while selectively lifting the ratio of γ-globin mRNA in polysomes. Importantly, downregulation of RBM3 did not impair erythropoiesis progression, suggesting a safe and effective therapeutic strategy for SCD and β-thalassemia. Our findings identify RBM3 as a negative regulator of HbF expression and reveal it as a novel molecular target for modulating the fetal-to-adult hemoglobin switch, holding great promise for the treatment of SCD and β-thalassemia.
    Keywords:  BCL11A; Fetal hemoglobin; RBM3; Sickle cell disease; Β-Thalassemia
    DOI:  https://doi.org/10.1016/j.intimp.2025.116107
  2. Lancet Haematol. 2026 Jan;pii: S2352-3026(25)00320-5. [Epub ahead of print]13(1): e49-e54
    Management of transfusion-dependent β-thalassaemia in the era of novel therapies: a prioritisation-based matrix for settings with limited resources.
    Khaled M Musallam, Sujit Sheth, Maria Domenica Cappellini, Farrukh Shah, Stefano Rivella, Vijay G Sankaran, Kevin H M Kuo, Vip Viprakasit, Androulla Eleftheriou, Michael Angastiniotis, Franco Locatelli, Ali T Taher.
      β-thalassaemia is an inherited haemoglobinopathy characterised by ineffective erythropoiesis and chronic anaemia of varying severity, which is predominant in the region extending from the Mediterranean basin and Middle East towards southeast Asia. Patients with severe phenotypes require lifelong transfusions, iron overload monitoring, and chelation. Suboptimal management due to access challenges continues to be directly linked to increased morbidity and mortality in many regions. In the past few decades, an improved understanding of the underlying pathogenesis of β-thalassaemia has led to the development of several disease-modifying therapies and curative gene manipulation techniques. However, global disparities in access and the need for specialised expertise hinder their wide implementation, especially in resource-limited countries where more than 80% of patients live. Uncertainty about which biomarkers can predict patient response further complicates the selection of patients for treatment. Beyond the need for access programmes and pragmatic national health policies, patient prioritisation by treating physicians, informed by available evidence and expert opinion, is crucial for ensuring that a resource-cautious management approach is implemented. This Viewpoint provides a decision matrix to prioritise interventions by need, benefit, and risk in settings with inadequate access, and to identify alternatives when standard options are unavailable. It draws on the Thalassaemia International Federation guidelines, best available trial and real-world evidence, and expert consensus from virtual discussions among the authors (haematologists, bone marrow transplantation physicians, patient group representatives, translational scientists, and trialists).
    DOI:  https://doi.org/10.1016/S2352-3026(25)00320-5
  3. Clin Adv Hematol Oncol. 2025 Dec;23(9): 534-538
    The diagnosis and treatment of red cell membrane disorders: algorithm for the general hematologist.
    Theodosia A Kalfa.
      
  4. J Biomol Struct Dyn. 2025 Dec 31. 1-10
    Molecular dynamics insights into novel and nano-rare de novo mutations in the ribosomal proteins S19 and L26 causing Diamond-Blackfan anemia in Iranian patients.
    Teymoor Khosravi, Mohaddese Mohsenipour, Hanieh Mohtashamiasl, Elham Alimoradi, Reza Alibakhshi, Saba Lorestani, Morteza Oladnabi, Parham Nejati.
      Diamond-Blackfan anemia syndrome (DBAS) is a rare congenital ribosomopathy characterized by erythroid hypoplasia, congenital anomalies and increased malignancy risk. Although pathogenic variants in RPS19 are the most frequent cause of DBAS, mutations in RPL26 remain exceedingly rare. Here, we identified two novel de novo variants in unrelated Iranian patients: a frameshift mutation in RPL26 (c.36_39del, p.Ser12Argfs*26) and a missense mutation in RPS19 (c.184C > G, p.Arg62Gly). Both variants were absent from major population databases and classified as likely pathogenic/pathogenic according to ACMG guidelines. Conservation analyses highlighted functional importance at the affected residues, and segregation studies confirmed their de novo status. To gain mechanistic insights, we performed molecular dynamics (MD) simulations comparing wild-type and mutant proteins. The RPL26 variant resulted in a truncated, shorter and more flexible protein with reduced solvent accessibility and compact conformation, consistent with impaired ribosome assembly and destabilized p53 regulatory signaling. In contrast, the RPS19 variant induced a globally compact structure while preserving local flexibility and solvent exposure, suggesting altered rRNA binding as the primary pathogenic mechanism. Collectively, our findings expand the mutational spectrum of DBAS, underscore the critical role of RPL26 and RPS19 in ribosome biogenesis and demonstrate how MD simulations can provide decisive structural evidence supporting variant pathogenicity in rare ribosomopathies.
    Keywords:  Diamond-Blackfan anemia; RPL26 gene; RPS19 gene; molecular dynamics simulation; whole exome sequencing
    DOI:  https://doi.org/10.1080/07391102.2025.2606815
  5. J Med Case Rep. 2025 Dec 30. 19(1): 662
    Is occlusive retinal vascular disease linked to hereditary spherocytosis postsplenectomy? A case series.
    Frida Velcani, Shivesh Shah, Brian E Zaugg, Michael P Teske, Nikhil N Batra.
       BACKGROUND: To present two separate cases of occlusive retinal vascular disease with secondary cystoid macular edema in patients with a past medical history significant for hereditary spherocytosis and splenectomy.
    CASE PRESENTATION: We present two patients with atypical ocular changes in the setting of a distant history of splenectomy with underlying hereditary spherocytosis. The first patient is a 52-year-old Caucasian male with findings consistent with adult-onset Coats disease, predominantly presenting as type 1 macular telangiectasia. The second patient is a 79-year-old Caucasian female with acute branch retinal vein occlusion with a remote history of bilateral nonarteritic anterior ischemic optic neuropathy.
    CONCLUSION: There is limited literature exploring the association between retinal vascular disease, hereditary spherocytosis, and splenectomy. These cases highlight that the link between vascular events and a remote history of splenectomy remains inconclusive, especially in the absence of evidence to differentiate it from other potential diagnoses. Both patients in our cases had secondary macular edema, which responded to treatment with intravitreal antivascular endothelial growth factor medications.
    Keywords:  BRVO; Coats disease; Hereditary spherocytosis; Macular telangiectasia; Retinal occlusion; Splenectomy
    DOI:  https://doi.org/10.1186/s13256-025-05678-1
  6. Glob Med Genet. 2025 Dec;12(4): 100083
    Global comprehensive transcriptomic and proteomic analyses of murine terminal erythroid differentiation.
    Xiao-Yue Tang, Jia-Huan Chen, Ran Yang, Hong Fan, Ke Yang, Tao Ding, Qiao-Chu Wang, Ye-Hong Yang, Yue Wu, Zhi-Yi Zhang, Chun-Mei Shi, Xue-Hui Liu, Jiang-Feng Liu, Xiang Lv, Jun-Tao Yang.
       Background: Terminal erythroid differentiation (TED) is the maturation process of proerythroblasts into enucleated erythrocytes. Animal models are essential for studying red blood cell disorders.
    Methods: We isolated erythroblasts at different TED stages from mouse bone marrow using FACS and performed integrated multi-omics analyses.
    Results: We developed a stage-specific transcriptome and proteome profile, enhancing murine TED databases. The most significant changes occurred during the transition from proerythroblasts to basophilic erythroblasts, characterized by immune function suppression and activation of erythroid processes. Global gene and protein expression dynamics showed that orthochromatic erythroblasts exit the cell cycle, with transcription cofactors histone deacetylase 1(HDAC1), histone deacetylase 2(HDAC2), and cell division control protein 6 homolog (CDC6), playing key roles in cell cycle regulation. Additionally, autophagy was initiated at the basophilic stage, indicated by increased autophagy-related gene (ATG) mRNA levels and activation of autophagy marker proteins like microtubule associated protein 1 light chain 3 beta (LC3-I), optineurin (OPTN), and ATGs, including Atg7, Atg4b, Atg3, and Atg2b.
    Conclusions: Overall, we have generated a foundational murine transcriptome and proteome dataset, providing insights into the functional dynamics and regulatory mechanisms of terminal erythroid differentiation.
    Keywords:  Murine; Proteome; Terminal erythroid maturation; Transcriptome
    DOI:  https://doi.org/10.1016/j.gmg.2025.100083
  7. Anemia. 2025 ;2025 8899690
    Pregnancy Outcomes in Women With Thalassemia Trait: A Multicenter Cohort Study.
    Daria Chelysheva, Ameera Syed, Hannah Ruby, Anna Homeniuk, Anas Atrash, Feras Al Moussally.
       Introduction: Thalassemia trait generally has minimal clinical impact, but physiologic changes during pregnancy may increase the risk of anemia, transfusion requirements, and hypertensive disorders. Existing evidence on pregnancy outcomes in this population is limited, with some conflicting data. This study aims to evaluate pregnancy-related outcomes in patients with thalassemia trait using a large, multicenter database.
    Methods: For this retrospective cohort study, we used data from the TriNetX US Collaborative Network. Females aged 18-45 with ICD-10 codes indicating pregnancy (Z33.1, O00-O9A, Z34, or Z3A) were included. Patients with pregnancy and coexisting thalassemia trait (D56.3) were assigned to the thalassemia cohort (n = 22,913), while those without any thalassemia diagnosis comprised the nonthalassemia cohort (n = 5,611,147). Propensity score matching was performed to balance age, race/ethnicity, obesity, smoking status, essential hypertension, and Type 2 diabetes mellitus. After 1:1 matching, 22,770 patients remained in each cohort (total N = 45,540). Outcomes were assessed within 1 year of the index date, including anemia during pregnancy, blood transfusion, preeclampsia/eclampsia, cesarean delivery, venous thromboembolism (VTE), heart failure/cardiomyopathy, preterm delivery, intrauterine growth restriction (IUGR), and intrauterine fetal demise (IUFD). Risk ratios (RRs) with 95% confidence intervals (CIs) were calculated.
    Results: Thalassemia trait was associated with higher risks of anemia during pregnancy (RR: 3.00 and 95% CI: 2.87-3.13), needing blood transfusion (RR: 1.90 and 95% CI: 1.69-2.20), preeclampsia/eclampsia (RR: 1.54 and 95% CI: 1.47-1.61), cesarean delivery (RR: 1.43 and 95% CI: 1.36-1.51), preterm delivery < 37 weeks (RR: 1.40 and 95% CI: 1.31-1.65), and IUGR (RR: 1.96 and 95% CI: 1.72-2.23), all were statistically significant with a p < 0.001. Increased risk was also observed for VTE (RR: 1.57 and 95% CI: 1.12-2.20, p < 0.001) and IUFD (RR: 1.37 and 95% CI: 1.087-1.75, p < 0.001). No significant association was found with heart failure/cardiomyopathy (RR: 1.28 and 95% CI: 0.93-1.76, p = 0.124).
    Conclusion: Thalassemia trait in pregnancy was associated with increased rates of anemia, transfusion, and adverse maternal and fetal outcomes. Such adverse outcomes include pre-eclampsia/eclampsia, cesarean delivery, preterm birth and IUGR. These findings underscore the need for tailored peripartum care strategies in this high-risk population.
    DOI:  https://doi.org/10.1155/anem/8899690
  8. Int J Lab Hematol. 2025 Dec 30.
    Crossed Erythrocytes Agglutination Pattern Observed in a Patient With Hereditary Elliptocytosis.
    Márcio A W Melo, Cristina M Silveira, Maíra M Ribeiro, Gabriela S Arcanjo.
      
    DOI:  https://doi.org/10.1111/ijlh.70054
  9. Lancet Haematol. 2026 Jan;pii: S2352-3026(25)00297-2. [Epub ahead of print]13(1): e6-e7
    Thalassaemia clinical trials in war-stricken Lebanon: a story of struggle and resilience.
    Farouk Kabbara, Nicole Charbel, Joseph Klim, Sacha El Khoury, Hassan Fawaz, Suzanne Koussa, Rayan Bou-Fakhredin, Ali Taher.
      
    DOI:  https://doi.org/10.1016/S2352-3026(25)00297-2
  10. Lancet Haematol. 2026 Jan;pii: S2352-3026(25)00346-1. [Epub ahead of print]13(1): e1
    Thalassaemia: advocacy, resilience, and adaptability.
    The Lancet Haematology.
      
    DOI:  https://doi.org/10.1016/S2352-3026(25)00346-1
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