bims-conane 2025-01-12 papers

Acta Biochim Biophys Sin (Shanghai). 2025 Jan 06.

MYB represses ζ-globin expression through upregulating ETO2.

Zejun Dong, Yuhua Ye, Wei Zhang, Hualei Luo, Jialong Li, Qianqian Zhang, Xinhua Zhang, Xiang Guo, Xiangmin Xu.

Reactivating the embryonic ζ-globin gene represents a potential therapeutic approach to ameliorate the severe clinical phenotype of α-thalassemia and sickle cell disease. The transcription factor MYB has been extensively proven to be a master regulator of the γ-globin gene, but its role in the regulation of ζ-globin remains incompletely understood. Here, we report a mechanistic study on the derepression of ζ-globin both in vivo and in vitro. We show that MYB depletion in mouse models and human hematopoietic stem cells leads to consistent and remarkable reactivation of ζ-globin. Furthermore, multiomics analysis and functional validation of MYB-knockout and wild-type cell lines reveal that ETO2 functions as a novel repressor of ζ-globin through coordination with NuRD nucleosome remodeling and the deacetylation complex to modulate histone deacetylation of ζ-globin. Additionally, we evaluate the clinical significance of these findings by knocking out ETO2 in primary CD34 + cells from nondeletional hemoglobin H patients, which results in a significant increase in ζ-globin expression. The RNA-seq data reveal that key erythroid genes are more co-regulated by Myb and Eto2 than by Myb and Klf1, highlighting a distinctly enhanced erythroid-specific transcriptional impact within the MYB-ETO2 regulatory axis. Compared with ETO2 knockout alone, codepletion of ETO2 and BCL11A did not significantly activate ζ-globin, suggesting that the MYB-ETO2 pathway primarily silences ζ-globin. Our study reveals a linear MYB-ETO2 signaling pathway crucial for ζ-globin repression and offers new targets for treating α-thalassemia and sickle cell disease.

Keywords: gene switch; hematopoiesis; thalassemia; zeta-globin

DOI: https://doi.org/10.3724/abbs.2024239

Genes (Basel). 2024 Dec 07. pii: 1576. [Epub ahead of print]15(12):

A Novel Pathogenic Sense Variant in Exon 7 of the HK1 Gene in a Patient with Hexokinase Deficiency and Gilbert Syndrome.

Magdalena Bartnik, Weronika Pawlik, Beata Burzyńska, Konrad Wasilewski, Elżbieta Kamieńska, Tomasz Urasiński.

BACKGROUND: Hexokinase (HK) deficiency is a rare autosomal recessively inherited disease manifested by chronic nonspherocytic hemolytic anemia. Most patients present with a mild to severe course of the disease (fetal hydrocephalus, neonatal hyperbilirubinemia, severe anemia). We reviewed 37 cases of patients with hexokinase deficiency described so far, focusing on the severity of the disease, clinical presentation, treatment applied, and genetic test results.
METHODS: We present a 10-year-old girl who initially presented with symptoms of weakness, excessive fatigue, and yellowing of the skin and sclerae. Genetic testing detected the (TA)7 variant in both alleles of the UGT1A1 gene and diagnosed Gilbert's disease. In the follow-up, red cell hemolysis was observed. The diagnosis was extended, and tests for red cell enzymopathy were performed and a reduced level of hexokinase-0.65 IU/gHb (normal 0.78-1.57) was found. Next-generation sequencing revealed a new sense-change variant in exon 7 in the hexokinase gene not previously reported in databases.
RESULTS: Up to this date, only around 37 cases of hexokinase deficiency associated with hereditary nonspherocytic hemolytic anemia have been documented around the world. Diagnosing hexokinase deficiency involves clinical evaluation, laboratory testing, and genetic analysis. Management focuses on treating symptoms and preventing complications; there is no cure for the underlying enzyme deficiency. In patients with severe anemia, the treatment is multiple blood transfusions followed by iron chelation therapy.
CONCLUSIONS: Understanding and diagnosing hexokinase deficiency is critical for providing appropriate care and improving the quality of life for affected individuals.

Keywords: HK1 gene; children; hemolytic anemia; hexokinase deficiency; next-generation sequencing

DOI: https://doi.org/10.3390/genes15121576

J Family Med Prim Care. 2024 Dec;13(12): 5847-5852

Prevalence of peripheral neuropathy in children with transfusion-dependent thalassemia: A hospital-based cross-sectional study.

Aniruddha Rathore, Mukesh Dhankar, Sharmila B Mukherjee, Suvasini Sharma, Shailaja Shukla, Piali Mandal.

Background: Our study aimed to determine the prevalence of Peripheral Neuropathy (using nerve conduction studies (NCS)) in children with transfusion-dependent thalassemia aged between 5 to 18 years and to study its correlation with chronic anemia, ferritin levels, chelation status, annual transfusion requirement, deficiency of serum Vitamin B12, and Folate levels.
Methods: In this hospital-based cross-sectional study, 100 eligible children were enrolled in a tertiary care teaching hospital in New Delhi, India. Neurological examinations focusing on peripheral neuropathy followed by NCS were performed on all the patients. Age-wise cutoff values outside of 2.5 SD of normal were taken as abnormal.
Results: None of the children had clinical features of peripheral neuropathy, although 77% had abnormalities in NCS. Of these, 33% had pure motor nerve changes, 7% had pure sensory nerve changes, 1% had abnormal F responses, and 26% had mixed nerve changes. These changes correlated significantly with chronic anemia and duration of iron chelation but not with other factors.
Conclusion: In children with transfusion-dependent thalassemia who do not exhibit any neurological signs or symptoms, however, it is not uncommon to observe abnormal NCS at an average hemoglobin (Hb) level of less than 9.5 g/dl. Further comprehensive case-control studies are necessary to determine if a more specific Hb target range of 9.5 to 10.5 g/dl is appropriate and to investigate the potential impact of chelation therapy on these changes.

Keywords: Anaemia; peripheral neuropathy; transufuison dependent thalaseemia

DOI: https://doi.org/10.4103/jfmpc.jfmpc_289_24

Transfus Apher Sci. 2025 Jan 03. pii: S1473-0502(24)00250-7. [Epub ahead of print]64(1): 104064

Long-term complications, survival and mortality in splenectomised adult transfusion-dependent thalassemia patients.

Urmimala Bhattacharjee, Alka Khadwal, Charanpreet Singh, Deepak Bansal, Amita Trehan, Thakur Deen Yadav, Arihant Jain, Gaurav Prakash, Prashant Sharma, Reena Das, Pankaj Malhotra.

BACKGROUND: Splenectomy is frequently performed in transfusion-dependent thalassemia (TDT) patients to lower blood transfusion needs but is associated with significant long-term complications, including sepsis, thrombosis, and pulmonary hypertension. This study examines the long-term complications, survival rates, and causes of mortality among adult patients with TDT who have undergone splenectomy in a low and middle-income country (LMIC).
METHODS: A retrospective analysis was conducted on 103 adult TDT patients (≥18 years) who underwent splenectomy between July 2013 and March 2024. Data collected included demographic and clinical characteristics, haematological parameters, transfusion requirements before splenectomy and at the last follow-up, survival rates, complications, and mortality causes.
RESULTS: The median age at splenectomy was 12 years (range 5-34). The majority (98 %) underwent open splenectomy. The yearly transfusion volume decreased from 276.7 ml/kg/year pre-splenectomy (range 207-433) to 146.2 (range 0-252.9) post-splenectomy at the last follow-up, p < 0.0001. Three patients were completely transfusion-free at the last follow-up. Complications included pulmonary hypertension in 10 (9.7 %), thrombosis in 5 (4.8 %), and overwhelming post-splenectomy infection (OPSI) in 4 (3.9 %). The iron-overload-related complications included cardiomyopathy in 17 (16.5 %), endocrinopathy in 56 (54.3 %), chronic liver disease in 15 (14.5 %) and hepatocellular carcinoma in 2 (0.9 %). The 15-year post-splenectomy overall survival (OS) was 84.7 % (95 % CI- 77.3 % - 92.8 %), with 17 deaths (16.5 %) recorded. Iron-overload-related cardiomyopathy was the leading cause of death in 8 (53.3 %).
CONCLUSION: Splenectomy significantly reduces transfusion requirements in TDT patients but is associated with risks such as thrombosis, pulmonary hypertension, and OPSI. Long-term mortality is primarily driven by iron-overload-related cardiomyopathy.

Keywords: Overwhelming post-splenectomy infection; Pulmonary hypertension; Splenectomy; Thrombosis; Transfusion-dependent thalassemia

DOI: https://doi.org/10.1016/j.transci.2024.104064

Int J Mol Sci. 2024 Dec 12. pii: 13314. [Epub ahead of print]25(24):

P2 Receptor Antagonists Rescue Defective Heme Content in an In Vitro SLC25A38-Associated Congenital Sideroblastic Anemia Cell Model.

Antonella Santoro, Silvia De Santis, Ferdinando Palmieri, Angelo Vozza, Gennaro Agrimi, Immacolata Andolfo, Roberta Russo, Antonio Palazzo, Clelia Tiziana Storlazzi, Arianna Ferrucci, Yong Woong Jun, Eric T Kool, Giuseppe Fiermonte, Achille Iolascon, Eleonora Paradies, Carlo Marya Thomas Marobbio, Luigi Palmieri.

Mutations in the SLC25A38 gene are responsible for the second most common form of congenital sideroblastic anemia (CSA), a severe condition for which no effective treatment exists. We developed and characterized a K562 erythroleukemia cell line with markedly reduced expression of the SLC25A38 protein (A38-low cells). This model successfully recapitulated the main features of CSA, including reduced heme content and mitochondrial respiration, increase in mitochondrial iron, ROS levels and sensitivity to oxidative stress. Notably, our study uncovered a new role for extracellular pyridoxal 5'-phosphate (PLP) and other P2 receptor antagonists in rescuing the altered parameters of A38-low cells (for example, the heme content of the A38-low cells was increased from about 50% to about 80% by the P2 receptor antagonists treatment compared with the value of the controls). These findings suggest that targeting P2 receptors could represent a promising therapeutic approach for SLC25A38-associated CSA.

Keywords: P2 receptors; SLC25A38; congenital sideroblastic anemia (CSA); heme biosynthesis; iron dyshomeostasis; mitochondrial carriers; oxidative stress; pyridoxal 5′-phosphate

DOI: https://doi.org/10.3390/ijms252413314