bims-conane 2025-05-04 papers

bims-conane

Biomed News

on Congenital anemias

Issue of 2025–05–04
six papers selected by
João Conrado Khouri dos Santos, Universidade de São Paulo

RNA Editors Sculpt the Transcriptome During Terminal Erythropoiesis.
Adenosine signaling in promoting the balance between erythropoiesis and myelopoiesis.
Dehydrated Hereditary Stomatocytosis (DHS): A Rare Inherited Hemolytic Disorder With Unusual Hypochromic Microcytic Anemia.
Drugs Repurposing of Molecules Modulating Human Delta Globin Gene Expression via a Model of Transgenic Foetal Liver Cells: Implications for Beta-Hemoglobinopathy Therapeutics.
Hepatobiliary Manifestations in Thalassemia Patients: A Narrative Review.
Clinical associations and potential cellular mechanisms linking G6PD deficiency and atherosclerotic cardiovascular disease.

Res Sq. 2025 Apr 24. pii: rs.3.rs-6355281. [Epub ahead of print]

RNA Editors Sculpt the Transcriptome During Terminal Erythropoiesis.

George Daley, Areum Han, Alena Yermalovich, Mohamad Ali Najia, Daniel Pearson, Yuko Fujiwara, Michael Bolgov, Caroline Kubaczka, Trista North, Vanessa Lundin, Stuart Orkin.

Selective RNA degradation during terminal erythropoiesis results in a globin-rich transcriptome in mature erythrocytes, but the specific RNA decay pathways remain unknown. We found that deficiency of the terminal uridylyl transferase enzyme Zcchc6 and the 3'-5' exoribonuclease Dis3l2 in mouse models led to fetal and perinatal reticulocytosis, an accumulation of RNA-rich precursors of terminal erythroid cells, suggesting their crucial roles in terminal red cell differentiation. Notably, knockout embryos exhibited persistent high-level expression of Hbb-bh1 globin, the ortholog of human fetal γ-globin. Perturbation of the Zcchc6-Dis3l2 pathway in mice engineered to express the human β-globin locus likewise increased γ-globin levels in fetal erythroid cells, suggesting that globin switching entails post-transcriptional mechanisms of mRNA destabilization in addition to transcriptional down-regulation. We cultured human hematopoietic stem and progenitor cells (HSPCs), performed CRISPR/Cas9-mediated knockout of ZCCHC6 and DIS3L2, and observed accumulation of RNA and elevated γ-globin levels in terminal erythroid cells. Our findings reveal a conserved role for the ZCCHC6/DIS3L2 RNA editors in terminal erythropoiesis and demonstrate a post-transcriptional mechanism for γ-globin gene switching, advancing research into in vitro erythrocyte generation and γ-globin stabilization to ameliorate hemoglobinopathies.

DOI: https://doi.org/10.21203/rs.3.rs-6355281/v1
Curr Opin Hematol. 2025 Apr 24.

Adenosine signaling in promoting the balance between erythropoiesis and myelopoiesis.

Mahmoud Mikdar, Marion Serra, Slim Azouzi.

   PURPOSE OF REVIEW: Adenosine signaling is emerging as a key regulator of hematopoietic lineage commitment, influencing both erythropoiesis and myelopoiesis. This review explores the distinct roles of adenosine receptors in balancing these processes, particularly under stress conditions. Since adenosine extracellular levels are increased in multiple hematological disorders, including sickle cell disease, deciphering the mechanisms downstream of adenosine receptor activation is crucial to understand the pathophysiology of these conditions.
RECENT FINDINGS: Extracellular adenosine levels in the bone marrow microenvironment are tightly regulated by CD39/CD73 activity and ENT1 uptake. Recent studies have shown that ENT1-mediated adenosine transport is crucial for adenosine intracellular metabolism and normal erythropoiesis, while increased extracellular adenosine levels impact hematopoietic differentiation through adenosine receptor activation.. High dose of exogenous adenosine inhibits erythroid proliferation by inducing G1 arrest and p53-mediated apoptosis. Furthermore, A2B and A3 receptor signaling inhibits erythroid differentiation, while adenosine signaling through A3 also favors granulopoiesis.
SUMMARY: Collectively, these findings highlight adenosine signaling as a critical and multifaceted regulator of hematopoietic balance, offering novel insights into its therapeutic potential for managing disorders characterized by ineffective erythropoiesis and aberrant myelopoiesis.

Keywords:  adenosine receptors; adenosine signaling; erythropoiesis; myelopoiesis; sickle cell disease

DOI:  https://doi.org/10.1097/MOH.0000000000000872
Cureus. 2025 Mar;17(3): e81335

Dehydrated Hereditary Stomatocytosis (DHS): A Rare Inherited Hemolytic Disorder With Unusual Hypochromic Microcytic Anemia.

Badriah G Alasmari, Shady Wafa, Amjad Alsari Alqahtani, Bahaa Sameh, Lina Elzubair.

  Dehydrated hereditary stomatocytosis (DHS) is an autosomal dominant (AD), non-immune hemolytic disorder due to increased erythrocyte membrane cation permeability that leads to red blood cell (RBC) dehydration and lysis, which can present with a wide range of clinical findings. DHS can be present with silent-to-mild normocytic or macrocytic anemia, increased risk of thrombotic complications, or partially compensated hemolysis with few symptoms. Senicapoc has been used recently to treat DHS as it showed activity against RBC dehydration in vitro; however, its clinical outcome is not established. In this study, we report an unusual case of a 10-year-old male child who was misdiagnosed with iron deficiency anemia (IDA) for three years, despite persistent anemia and unresponsiveness to iron therapy. The diagnosis was done using whole exome sequencing (WES).

Keywords:  dehydrated hereditary stomatocytosis; microcytic hypochromic anemia; non-immune hemolytic disorder; piezo1 mutations; pseudohyperkalemia

DOI:  https://doi.org/10.7759/cureus.81335
Biomolecules. 2025 Apr 11. pii: 565. [Epub ahead of print]15(4):

Drugs Repurposing of Molecules Modulating Human Delta Globin Gene Expression via a Model of Transgenic Foetal Liver Cells: Implications for Beta-Hemoglobinopathy Therapeutics.

Michela Simbula, Maria Francesca Manchinu, Stefania Olla, Michela Congiu, Simona Vaccargiu, Cristian Antonio Caria, Daniela Poddie, Maria Serafina Ristaldi.

  Beta-hemoglobinopathies such as beta-thalassemia and sickle cell disease are severe genetic blood disorders affecting the beta globin chain of haemoglobin A (α2β2). Activation of delta globin, the non-alpha globin of HbA2 (α2δ2), could represent a possible approach to improve the clinical severity of these pathologies. Notably, the therapeutic potential of delta globin has been demonstrated in previous studies using a mouse model of beta-thalassemia and sickle cell disease. The present study evaluated delta globin gene activation by small molecules in erythroid cells isolated from transgenic murine foetal liver. A screening of 119 molecules, selected for their potential in drug repurposing, was performed without prior selection based on specific pathways of interest. Three candidates-Nexturastat, Stattic and Palbociclib-were found to have high efficacy on delta globin expression. Palbociclib also proved effective in increasing gamma globin expression. All of these compounds have pharmacokinetic profiles that are beneficial for clinical application, providing potential inducer agents of HbA2 that could have therapeutic effects in the treatment of beta-hemoglobinopathies.

Keywords:  beta-thalassemia; delta globin gene; drug assay; sickle cell disease

DOI:  https://doi.org/10.3390/biom15040565
Hemoglobin. 2025 Apr 28. 1-8

Hepatobiliary Manifestations in Thalassemia Patients: A Narrative Review.

Asha Tiwari, Ekta Rao, Iswarya Suresh, Manish Tiwari, Ravindra Kumar.

  Thalassemia is one of the most common inherited blood disorders worldwide. This defect causes a disproportionate ratio of α- and β-globin chains resulting in ineffective erythropoiesis leading to increased iron absorption. In patients where the imbalance between α and β globin chains is great they are dependent on blood transfusions for survival. This results in transfusional iron overload but also comes with additional risks such as transfusion-transmissible viral infections like hepatitis B and C. This can lead to various complications like liver fibrosis, cirrhosis and hepatocellular carcinoma, which are important causes with morbidity and mortality in patients of thalassemia today. These hepatobiliary manifestations and their management are briefly discussed in this review. Understanding hepatobiliary complications in thalassemia is vital for optimizing patient care.

Keywords:  HBV; HCV; Thalassemia; hepatobiliary complications; iron overload

DOI:  https://doi.org/10.1080/03630269.2025.2493946
NPJ Metab Health Dis. 2025 ;3(1): 16

Clinical associations and potential cellular mechanisms linking G6PD deficiency and atherosclerotic cardiovascular disease.

Patrick H Andrews, James C Zimring, Coleen A McNamara.

  Glucose 6-phosphate dehydrogenase deficiency (G6PD-d) is the most common enzymopathy in the world, occurring in 5-8% of the global population (half a billion people). Recent epidemiological evidence suggests that G6PD-d may be associated with increased cardiovascular disease (CVD). Atherosclerosis is the dominant cause of CVD, including myocardial infarction, heart failure, stroke, and peripheral artery disease. Atherosclerosis, in turn, is a chronic inflammatory disease, fueled by oxidized lipids and influenced by various immune and nonimmune cells including vascular endothelial and smooth muscle cells, monocytes and macrophages, T cells, B cells, and red blood cells. Here, we review the existing epidemiological evidence supporting a role for G6PD-d in CVD in humans and explore the data on potential cellular mechanisms by which G6PD-d may exacerbate atherosclerosis.

Keywords:  Diseases; Dyslipidaemias

DOI:  https://doi.org/10.1038/s44324-025-00061-6