bims-conane 2025-02-16 papers

Blood Cells Mol Dis. 2025 Feb 07. pii: S1079-9796(25)00002-6. [Epub ahead of print]111 102910

Hereditary disorders of ineffective erythropoiesis.

Under steady state conditions, humans must produce ∼2 million red blood cells per second to sustain normal red blood cell counts and hemoglobin levels. Ineffective erythropoiesis, also termed dyserythropoiesis, is a process by which erythroid precursors die or fail to efficiently differentiate in the bone marrow. Ineffective erythropoiesis is characterized by expanded bone marrow erythropoiesis and increased erythroferrone production by bone marrow erythroblasts, with the latter resulting in reduced hepcidin production and increased iron absorption. Ineffective erythropoiesis may result from acquired and congenital conditions. Inherited causes of ineffective erythropoiesis include β-thalassemia, sideroblastic anemias, pyruvate kinase deficiency, and congenital dyserythropoietic anemias. This manuscript reviews the definition and evidence for ineffective erythropoiesis and describes the most common hereditary disorders of dyserythropoiesis.

Keywords: Congenital dyserythropoietic anemia; Dyserythropoiesis; Erythropoiesis; Ineffective erythropoiesis; Red blood cells

DOI: https://doi.org/10.1016/j.bcmd.2025.102910

Front Pediatr. 2025 ;13 1514722

Cardiac injury caused by iron overload in thalassemia.

Chunxi Fu, Xue Yang.

Cardiac iron overload affects approximately 25% of patients with β-thalassemia major, which is associated with increased morbidity and mortality. Two mechanisms are responsible for iron overload in β-thalassemia: increased iron absorption due to ineffective erythropoiesis and blood transfusions. This review examines the mechanisms of myocardial injury caused by cardiac iron overload and role of various clinical examination techniques in assessing cardiac iron burden and functional impairment. Early identification and intervention for cardiac injury and iron overload in β-thalassemia have the potential to prevent and reverse or delay its progression in the early stages, playing a crucial role in its prognosis.

Keywords: early identification; iron overload; myocardial injury; treatment; β-thalassemia

DOI: https://doi.org/10.3389/fped.2025.1514722

JPGN Rep. 2025 Feb;6(1): 56-59

Drug-induced liver injury from Deferasirox in a pediatric patient with hereditary spherocytosis: A case report.

Siddhant Talwar, Blake Rosenthal, Madhav Vissa, Kayla Cort, Joshua Byers, Sabina Ali.

Patients with hereditary spherocytosis (HS) often require red blood cell transfusions for the treatment of hemolytic anemia. Iron overload is a known complication of frequent transfusions. Deferasirox, an oral iron chelator, can cause transient elevations in serum aminotransferase levels. There have been a few cases demonstrating Deferasirox-associated liver injury in patients with sickle cell anemia and thalassemia. In this case report, we present a 13-year-old male with transfusion-dependent HS treated with Deferasirox who presented with jaundice and was found to have evidence of acute hepatocellular injury.

Keywords: anemia; chelation; hepatocellular injury; hyperbilirubinemia

DOI: https://doi.org/10.1002/jpr3.12155

Ann Hematol. 2025 Feb 10.

Systematic identification and validation of ceRNA-driven regulatory mechanisms in pediatric β-Thalassemia major.

Tao Wu, Zhenmin Ren, Xiaorong Liu, Zhihao Xing, Xiaoying Fu, Wujiao Li, Moxian Chen, Defa Li, Yunsheng Chen.

Reactivation of fetal hemoglobin (Hb F, α2γ2) has been demonstrated to be a therapeutic strategy for patients with β-hemoglobinopathies. MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression by silencing RNA. Both coding and non-coding RNAs can compete for the same miRNAs, acting as competing endogenous RNAs (ceRNAs). However, the role of ceRNAs in β-thalassemia major (β-TM) and their impact on γ-globin expression remains poorly understood. In this study, we conducted transcriptome sequencing to collect circularRNA (circRNA), miRNA, and mRNAs from β-TM patients and healthy individuals. Through bioinformatics analysis, we constructed a GATA2‑associated ceRNA network, emphasizing the hsa_circ_0005245_hsa-miR-425-3p_GATA2 pathway. Validation using qRT-PCR analysis in β-TM samples, RNA immunoprecipitation, and dual-luciferase reporter assays confirmed this pathway. Furthermore, overexpression of hsa_circ_0005245, hsa-miR-425-3p, and GATA2 in HUDEP-2 cells individually resulted in elevated γ-globin levels. Our findings identify a novel hsa_circ_0005245_hsa-miR-425-3p_GATA2 pathway that regulates γ-globin expression, providing potential insights for the clinical management of β-TM patients.

Keywords: GATA2 ; CeRNA; β-thalassemia major; γ-globin

DOI: https://doi.org/10.1007/s00277-025-06215-2

Blood Adv. 2025 Feb 10. pii: bloodadvances.2024015232. [Epub ahead of print]

Cellular and biochemical heterogeneity contributes to the phenotypic diversity of transfusion-dependent beta thalassemia.

Transfusion-dependent thalassemia (TDT) is a type of protein aggregation disease. Its clinical heterogeneity imposes challenges in effective management. Red blood cell (RBC) variables may be clinically relevant as mechanistic parts or tellers of TDT pathophysiology. This is a cross-sectional study of RBC and plasma physiology in adult TDT subjects versus healthy control. TDT plasma was characterized by increased protein carbonylation, antioxidants, and larger than normal extracellular vesicles. RBCs were osmotically resistant but prone to oxidative hemolysis. They overexposed phosphatidylserine and exhibited pathologically low proteasome proteolytic activity (PPA), that correlated with metabolic markers of the disease. RBC ultrastructure was distorted, with splenectomy-related membrane pits of 300-800 nm. Plasma metabolomics revealed differences in heme metabolism, redox potential, short-chain fatty acids, and NO bioavailability, but also in catecholamine pathways. According to coefficient of variation assessment, hemolysis, iron homeostasis, PPA and phosphatidylserine exposure were highly variable among patients, as opposed to RBC fragility, and plasma antioxidants, amino acids, and catecholamines. Sex-based differences were detected in hemolysis, redox and energy variables, while splenectomy-related differences referred to thrombotic risk, RBC morphology, and plasma metabolites with neuroendocrine activity. Hepcidin varied according to oxidative hemolysis and metabolic markers of bacterial activity. Subjects with higher (>10 g/dL) pretransfusion Hb levels presented mildly distorted profiles and lower membrane-associated PPA, while classification by severity of mutations revealed different levels of hemostasis, inflammation, plasma epinephrine, hexosamines, and methyltransferase activity markers. The currently reported heterogeneity of cellular and biochemical features probably contributes to the wide phenotypic diversity of TDT at clinical level.

DOI: https://doi.org/10.1182/bloodadvances.2024015232

Transfus Apher Sci. 2025 Feb 04. pii: S1473-0502(25)00026-6. [Epub ahead of print]64(2): 104092

CAPRIN2 RNA-binding protein contributes to balance erythroid production: Implications in the fine-tuning of proteostasis during erythropoiesis.

Zacaria Jaiteh, Reinier van der Linden, John Kong-A-San, Alex Maas, Sjaak Philipsen, Frank Grosveld, Laura Gutiérrez.

Erythropoiesis is a process that requires tight control of gene transcription, mRNA stability, and protein synthesis and degradation. These regulatory layers adapt dynamically to developmental needs and physiological stresses, ensuring precise control of erythroid production. Ribosomopathies, such as Diamond-Blackfan anemia (DBA), are characterized by defects in ribosome function. Zooming in on erythroid precursors, ribosomopathies lead to dysregulated translation of mRNAs encoding specific and essential erythropoietic genes, including master transcription factors such as GATA1. This causes defective maturation and increased apoptosis of erythroid progenitors, and consequently, anemia. Beyond ribosomal proteins, RNA-binding proteins have been put forward as an additional and targeted checkpoint regulating cellular proteostasis. CAPRIN2, which is present in neurons and erythroid cells, is one such RNA-binding protein, involved in RNA translation regulation and its levels rise during terminal erythroid differentiation. Overexpression of CAPRIN2 in Chinese hamster ovary (CHO) cells causes reduced growth, cell cycle arrest, and apoptosis. Here, we demonstrate that GATA1 potentially regulates Caprin2 transcription, and that Caprin2 loss boosts erythroid production and maturation during gestation and adulthood, a phenomenon that is enhanced in situations of stress erythropoiesis. Our results provide new insight into the role of CAPRIN2 in erythropoiesis. We hypothesize that it regulates the translation of key mRNAs during erythropoiesis. We propose that CAPRIN2 is involved in the balance of erythroid production and that its manipulation may control erythroid production, offering a potential and promising approach to manage altered erythropoiesis.

Keywords: CAPRIN2; Erythropoiesis; Proteostasis; RNA translation; RNA-binding protein; Stress erythropoiesis

DOI: https://doi.org/10.1016/j.transci.2025.104092