bims-conane 2025-09-28 papers

bims-conane

Biomed News

on Congenital anemias

Issue of 2025–09–28
eight papers selected by
João Conrado Khouri dos Santos, Universidade de São Paulo

Coexistence of Hereditary Spherocytosis, Beta-Thalassemia Trait and Gilbert Syndrome in a Newborn: A Rare Genetic Profile.
Inhibition of XPO1 by selinexor enhances terminal erythroid maturation through modulation of HSP70 trafficking in severe β0-thalassemia/HbE.
Haploidentical hematopoietic stem cell transplantation for the treatment of congenital dyserythropoietic anemia combined with thalassemia: a report of two cases.
Association Between KLF1, BCL11A and HBS1L-MYB Polymorphisms and Phenotypes With β-Thalassemia Patients in Hainan.
Hereditary Spherocytosis: Review of Presentation at Birth.
EKLF/KLF1 coordinates specialized transcriptional networks required to maintain the integrity of terminal erythropoiesis.
Elevated serum heme oxygenase-1 in pediatric sickle cell disease: Insights from the SickleGenAfrica Network.
Germline mosaicism in a family affected by Diamond-Blackfan anaemia.

Fetal Pediatr Pathol. 2025 Sep 27. 1-5

Coexistence of Hereditary Spherocytosis, Beta-Thalassemia Trait and Gilbert Syndrome in a Newborn: A Rare Genetic Profile.

Sanjana Kapoor, Priyanka Gupta.

  Introduction: Hereditary spherocytosis (HS) is a congenital hemolytic anemia, often under-recognized in neonates. Co-inheritance with other genetic disorders like Gilbert syndrome (GS) and beta-thalassemia trait (BTT) can complicate the diagnosis. Case Report: We report a neonate presenting with significant unconjugated hyperbilirubinemia and anemia. Genetic testing revealed a triple diagnosis- HS due to a heterozygous deletion in the SPTB gene, BTT with a splice-site variant in the HBB gene, and heterozygosity for UGT1A1 promoter polymorphism associated with GS. The father, previously diagnosed with GS, was also found to have HS, explaining his long-standing splenomegaly and history of cholelithiasis. Conclusion: This rare triple genetic diagnosis highlights the need for comprehensive evaluation of neonatal jaundice and anemia, considering combined hemolytic, enzymatic and hemoglobinopathy causes. Detailed clinical evaluation of family members is crucial to avoid missed diagnoses.

Keywords:  Beta-thalassemia trait; Gilbert syndrome; genetic diagnosis; hereditary spherocytosis; neonatal jaundice

DOI:  https://doi.org/10.1080/15513815.2025.2565487
PLoS One. 2025 ;20(9): e0333127

Inhibition of XPO1 by selinexor enhances terminal erythroid maturation through modulation of HSP70 trafficking in severe β0-thalassemia/HbE.

Pinyaphat Khamphikham, Adisak Tantiworawit, Songyot Anuchapreeda.

Ineffective erythropoiesis is a hallmark of β-thalassemia, characterized by impaired erythroid maturation and increased apoptosis of erythroid precursors in the bone marrow, resulting in chronic anemia. Heat shock protein 70 (HSP70) trafficking has emerged as a critical regulator of erythroid maturation. Inhibition of nuclear export protein exportin-1 (XPO1) retains HSP70 in the nucleus, thereby promoting terminal erythroid maturation (TEM) through stabilization of the transcription factor GATA1. In this study, we screened nine XPO1 inhibitors, including the natural compounds curcumin, piperlongumine, plumbagin, and oridonin, as well as the synthetic agents KPT-185, KPT-276, selinexor, verdinexor, and eltanexor, in erythroid progenitors from patients with severe β0-thalassemia/HbE to identify the most effective inducer of TEM and to investigate the downstream molecular mechanisms involved. Selinexor, an FDA-approved drug for multiple myeloma, showed the greatest efficacy in enhancing TEM across nine independent patient samples without altering hemoglobin composition. Combination treatments with hydroxyurea (a γ-globin inducer) and SIS3 (a SMAD3 inhibitor) confirmed selinexor's dominant effect. Mechanistically, selinexor-induced TEM was associated not only with stabilization of nuclear HSP70 and GATA1 but also with a dose-dependent increase in cytoplasmic HSP70. These findings suggest that cytoplasmic HSP70 trafficking may contribute to erythroid maturation in severe β0-thalassemia/HbE, implicating regulatory pathways beyond nuclear GATA1 stabilization. Collectively, our findings highlight the therapeutic potential of repurposing selinexor to enhance erythroid maturation in β-thalassemia and suggest that cytoplasmic HSP70 trafficking warrants further investigation as a contributor to terminal erythroid maturation in β-thalassemia.

DOI: https://doi.org/10.1371/journal.pone.0333127
Ann Hematol. 2025 Sep 26.

Haploidentical hematopoietic stem cell transplantation for the treatment of congenital dyserythropoietic anemia combined with thalassemia: a report of two cases.

Changyu Yang, Jian Huang, Kun Yang, Changqing Wei, Lina Lu, Dongmei Liu, Beibei Yang, Guiping Liao, Xiaolin Yin, Yali Zhou.

  Congenital dyserythropoietic anemia (CDA) represents a heterogeneous group of rare hereditary disorders characterized by ineffective erythropoiesis and often presents with clinical features that overlap with thalassemia. Hematopoietic stem cell transplantation (HSCT) remains the only definitive curative intervention for CDA; however, the application of haploidentical HSCT in this context is limited and presents considerable challenges. Herein, we report two pediatric cases of CDA coexisting with thalassemia who underwent haploidentical related donor HSCT utilizing a novel conditioning regimen comprising three alkylating agents. Graft-versus-host disease (GVHD) prophylaxis was achieved using. posttransplant cyclophosphamide and anti-thymocyte globulin. Both patients attained sustained engraftment, transfusion independence, and remained free from severe transplant-related complications. These cases illustrate the feasibility and therapeutic potential of haploidentical HSCT for CDA, even in. the presence of concomitant thalassemia.

Keywords:  Anti-thymocyte globulin; Congenital dyserythropoietic anemia; Hematopoietic stem cell transplantation; Posttransplant cyclophosphamide; Thalassemia

DOI:  https://doi.org/10.1007/s00277-025-06615-4
Mol Genet Genomic Med. 2025 Sep;13(9): e70142

Association Between KLF1, BCL11A and HBS1L-MYB Polymorphisms and Phenotypes With β-Thalassemia Patients in Hainan.

Junjie Hu, Huaye Chen, Wei Gong, Min Feng, Shidong Fu, Weihua Xu, Zhichao Ma, Shengmiao Fu, Xinping Chen.

   BACKGROUND: The factors influencing the phenotypic heterogeneity of patients with β-thalassemia have been receiving much attention in the field of hematology research. Activating the sustained expression of fetal hemoglobin (HbF) has proven to be one of the effective ways to alleviate the clinical symptoms of β-thalassemia. Studies have reported that single nucleotide polymorphisms (SNP) in KLF1, BCL11A, and HBS1L-MYB can increase the expression level of HbF in patients with β-thalassemia and have an impact on the phenotype.
METHODS: In this study, SNaPshot and Sanger sequencing were used to detect SNPs of BCL11A, HBS1L-MYB, and KLF1 in patients with different types of β-thalassemia collected in Hainan. Linkage disequilibrium and haplotype analysis were performed on mutant sites.
RESULTS: As a result, 41 mutation types of the above genes were detected (high mutation frequency and wide distribution range), and there was strong linkage disequilibrium at multiple mutation sites, resulting in multiple haplotypes. However, there are no significant differences in the distribution of gene polymorphisms between different types of β-thalassemia, suggesting that the modifications of KLF1, BCL11A, and HBS1L-MYB may have little impact on the β-thalassemia phenotype in this region.
CONCLUSION: Our study provides data support for assessing the impact of modified genes on the phenotype of patients with β-thalassemia in Hainan, and also promotes the clinical accurate diagnosis and classification evaluation of β-thalassemia.

Keywords:   BCL11A ; HBS1L‐MYB ; KLF1 ; β‐thalassemia

DOI:  https://doi.org/10.1002/mgg3.70142
Children (Basel). 2025 Sep 10. pii: 1207. [Epub ahead of print]12(9):

Hereditary Spherocytosis: Review of Presentation at Birth.

Nadine-Stella Achenjang, Elizabeth Jadczak, Rita M Ryan, Mary L Nock.

  Background/Objectives: We wished to raise awareness of Hereditary Spherocytosis (HS) as a potential cause of early and significant hemolytic newborn jaundice. Methods: We utilized three recent cases from our experience to discuss hyperbilirubinemia etiologies to be considered when a baby has hemolytic hyperbilirubinemia, including HS, and presented a review of the literature about this disorder including presentation and evaluation in the neonate. Results: We found that ABO hemolytic disease of the newborn (HDN) is often considered as the etiology for presumed hemolytic hyperbilirubinemia even when the direct antiglobulin test (DAT) is negative. When there is a mother-baby ABO mismatch and baby'sDAT is negative, another etiology should be sought. HS should be considered in these cases as the prevalence of HS is as frequent as 1 in 2000 in certain populations, it is the third most common hemolytic disorder after ABO isoimmunization and G6PD deficiency, and it is the most common cause of non-immune hemolytic hyperbilirubinemia in neonates with kernicterus. The indices to look for in the complete blood count that are suggestive for HS are MCHC > 36.5-37 g/dL, an MCHC:MCV ratio (HS Index) > 0.36, and increased RDW. The lack of spherocytes on the newborn peripheral blood smear, family history, initial anemia, and reticulocytosis do not eliminate the diagnosis of HS. Conclusions: HS is common and should be included in the differential diagnosis for hemolytic hyperbilirubinemia. Red blood cell indices can suggest the diagnosis of HS, and eosin 5' maleimide (EMA) testing can be used to make the diagnosis. If DAT-negative ABO HDN is the leading diagnosis for hyperbilirbinemia, a different etiology should urgently be sought.

Keywords:  G6PD deficiency; eosin 5’ maleimide; hyperbilirubinemia; jaundice; red blood cell hemolysis

DOI:  https://doi.org/10.3390/children12091207
J Cell Sci. 2025 Sep 22. pii: jcs.264036. [Epub ahead of print]

EKLF/KLF1 coordinates specialized transcriptional networks required to maintain the integrity of terminal erythropoiesis.

M N Gnanapragasam, P Jiang, A R Dhara, P N Patel, M Ramamoorthy, R B Nowak, V M Fowler, J J Bieker.

  Erythroid Krüppel Like Factor (EKLF/ KLF1) is a C2H2 zinc finger transcription factor that plays a critical role in all aspects of erythropoiesis. Mutations in KLF1 lead to diverse phenotypes ranging from mild to severe anemias. Patients with a heterozygous E325K mutation (CDA type IV) exhibit impaired erythroid terminal differentiation and increased presence of binucleate erythroblasts. We previously showed that KLF1 is necessary for cell cycle exit and enucleation in mouse primary cells. In the current study we discovered that genes involved in cell motility, cell division, and mitotic pathways are all directly regulated by KLF1. Klf1-/- cells exhibit increased numbers of binucleated erythroblasts and DNA bridges, and differentiating Klf1-/- erythroblasts display an increased percentage of cytokinesis failure events and defective microtubule bundling. Klf1-/- erythroblasts produce frequent aberrant F-actin-rich membrane protrusions and anucleate cell fragments. Human CDA type IV cells exhibit similar patterns of dysregulation of cytokinesis and cell motility genes. Collectively, we show that KLF1 is necessary for maintaining the integrity of erythroid cell divisions by direct regulation of genes involved in cytokinesis and motility pathways during terminal erythroid differentiation.

Keywords:  Cytokinesis; Enucleation; Erythropoiesis; Transcription

DOI:  https://doi.org/10.1242/jcs.264036
Hemasphere. 2025 Sep;9(9): e70209

Elevated serum heme oxygenase-1 in pediatric sickle cell disease: Insights from the SickleGenAfrica Network.

SickleGenAfrica Network

Sickle cell disease (SCD) is characterized by chronic hemolysis, resulting in the release of extracellular heme, which contributes to oxidative stress and inflammation. Heme oxygenase-1 (HO-1), an inducible enzyme that degrades heme into cytoprotective by-products, plays a critical role in mitigating heme-induced toxicity. This study analyzed serum HO-1 levels in 2309 individuals with SCD (53% female; median age: 12 years) from the SickleGenAfrica cohort, comprising 57% hemoglobin SS disease (Hb SS), 30% hemoglobin SC disease (Hb SC), 3.1% Hb sickle beta plus thalassemia (Sβ+ thalassemia), and 9.9% Hb S-hereditary persistence of fetal hemoglobin (Hb S-HPFH). Median HO-1 levels were threefold higher in children under 16 years (69.8 ng/mL; interquartile range [IQR]: 29.8-137.6) compared to adults (23.1 ng/mL; IQR: 7.8-62.4; P < 0.001), with peak levels observed in the 6-10-year age group. Across all subgroups, including sex, genotype, and hydroxyurea use, children consistently exhibited higher HO-1 levels than adults, with Hb SS patients showing the highest levels. Haptoglobin and hemopexin, key scavengers of hemoglobin and heme, respectively, were depleted in all patients, particularly in children. Overall, HO-1 levels in SCD patients were markedly elevated compared to healthy populations. These findings highlight the pronounced elevation of HO-1 in pediatric SCD patients, suggesting its potential protective role against heme-induced toxicity, especially during childhood.

DOI: https://doi.org/10.1002/hem3.70209
Br J Haematol. 2025 Sep 21.

Germline mosaicism in a family affected by Diamond-Blackfan anaemia.

Eoghan Dunlea, Sally Ann Lynch, Daniel Angelov, Melanie Cotter.



Keywords:  bone marrow failure; clinical genetics; diamond blackfan anaemia; paediatric haematology

DOI:  https://doi.org/10.1111/bjh.70173