bims-conane Biomed News
on Congenital anemias
Issue of 2024–10–20
seven papers selected by
João Conrado Khouri dos Santos, Universidade de São Paulo
  1. Hypercoagulability in hemoglobinopathies: Decoding the thrombotic threat.
  2. Hemoglobin Balkh, a Novel Mutation in Codon 132 of α2-Globin Gene [α132(H15) (+T) or HBA2:C.396dup (p.Val134fs)]: A Case Report and Insight into the Pathophysiology.
  3. Clinical implications of miRNAs in erythropoiesis, anemia, and other hematological disorders.
  4. Serum ferritin is a risk factor for pulmonary dysfunction in young patients with transfusion-dependent thalassemia.
  5. Lysine succinylation precisely controls normal erythropoiesis.
  6. δβ-Thalassemia and α-Triplication: Is Genetic Retesting Worthwhile in Case of Non-Coherent Phenotype?
  7. Erythroblast enucleation at a glance.
  1. Am J Hematol. 2024 Oct 14.
    Hypercoagulability in hemoglobinopathies: Decoding the thrombotic threat.
    Rayan Bou-Fakhredin, Maria Domenica Cappellini, Ali T Taher, Lucia De Franceschi.
      Beta (β)-thalassemia and sickle cell disease (SCD) are characterized by a hypercoagulable state, which can significantly influence organ complication and disease severity. While red blood cells (RBCs) and erythroblasts continue to play a central role in the pathogenesis of thrombosis in β-thalassemia and SCD, additional factors such as free heme, inflammatory vasculopathy, splenectomy, among other factors further contribute to the complexity of thrombotic risk. Thus, understanding the role of the numerous factors driving this hypercoagulable state will enable healthcare practitioners to enhance preventive and treatment strategies and develop novel therapies for the future. We herein describe the pathogenesis of thrombosis in patients with β-thalassemia and SCD. We also identify common mechanisms underlying the procoagulant profile of hemoglobinopathies translating into thrombotic events. Finally, we review the currently available prevention and clinical management of thrombosis in these patient populations.
    DOI:  https://doi.org/10.1002/ajh.27500
  2. Hemoglobin. 2024 Oct 16. 1-5
    Hemoglobin Balkh, a Novel Mutation in Codon 132 of α2-Globin Gene [α132(H15) (+T) or HBA2:C.396dup (p.Val134fs)]: A Case Report and Insight into the Pathophysiology.
    Shabnam Tavassoli, Jong H Chung, Arun R Panigrahi, Azadeh Shahsavar, Ashutosh Lal, Sylvia Titi Singer.
      We report a novel mutation on α2-globin gene leading to an elongated α-chain. This novel frameshift mutation was detected in a 13-year-old boy from Balkh province, Afghanistan. DNA analysis identified an insertion of thymine (T) at codon 132 [HBA2:c.396dup (p.Val134fs)]. We named the novel hemoglobin variant 'Hemoglobin Balkh' after the geographic location from which the patient originated. This novel variant was found in association with α3.7 kb α-globin gene deletion, suggesting a compound heterozygous state that contributes to the patient's clinical presentation.
    Keywords:  Unstable hemoglobin; alpha thalassemia; elongated α-globin chain; hemolytic anemia; non-deletional mutation
    DOI:  https://doi.org/10.1080/03630269.2024.2410295
  3. Mol Biol Rep. 2024 Oct 18. 51(1): 1064
    Clinical implications of miRNAs in erythropoiesis, anemia, and other hematological disorders.
    Jayanta Kumar Pal, Subhayan Sur, Smriti P K Mittal, Saurabh Dey, Monali Prakash Mahale, Arijit Mukherjee.
      Erythropoiesis is regulated by the differential expression of many genes. Besides being transcriptionally regulated, these genes are also with the oath of epigenetic regulation by the microRNAs (miRNAs), in particular. Various miRNAs appear to be very important for the normal process of erythropoiesis and various hematological abnormalities in humans. Therefore, the review aims to summarize the significance of miRNAs in erythropoiesis and different hematological diseases with clinical importance. Our analysis indicates that specific miRNAs regulate erythropoiesis in a stage-specific manner from hematopoietic stem cells to differentiated erythrocytes. Further, many miRNAs have been reported to be linked with various hematological diseases. The importance of miRNAs as biomarkers or therapeutic drug targets for various hematological disorders like anemia, β-thalassemia, and leukemia has been revealed through various clinical studies and clinical trials. The miR-34a mimic and miR-155 inhibitor demonstrate promising therapeutic effects in various hematological malignancies. Additionally, miR-34a, miR-538e, miR-193e, and miR-198 exhibit diagnostic potential in acute myeloid leukemia, while miR-451, miR-151-5p, and miR-1290 show diagnostic potential in B-cell acute lymphoblastic leukemia. Thus, this review encompasses the latest observations and implications of specific miRNAs in erythropoiesis and various hematological disorders. However, challenges persist in developing safe and efficient delivery strategies to target miRNAs specifically, minimizing off-target effects and enhancing therapeutic outcomes. Future mechanistic pre-clinical and clinical research would contribute to overcoming these challenges.
    Keywords:  Anemia; Diagnostic markers; Erythropoiesis; Leukemia; Microrna (miRNA); Therapeutic target
    DOI:  https://doi.org/10.1007/s11033-024-09981-w
  4. Heliyon. 2024 Oct 15. 10(19): e38069
    Serum ferritin is a risk factor for pulmonary dysfunction in young patients with transfusion-dependent thalassemia.
    Xiao Liang, Gaohui Yang, Lingling Shi, Lianjin Liu, Zhenbin Wei, Yumei Huang, Jing Bai, Yi Liang, Lingyuan Pan, Zhaoping Gan, Yu Lin, Yibin Yao, Ying Tang, Huicheng Huang, Xuemei Zhou, Yongrong Lai, Rongrong Liu.
      Research into the pulmonary function of patients with transfusion-dependent thalassemia (TDT) is limited, with existing studies presenting conflicting results. We carried out a retrospective study involving 140 patients with TDT. The mean patient age was 8.7 ± 3.2 years, with a median serum ferritin (SF) level of 3791.4 ng/ml (IQR: 2424.1-5733.3 ng/ml). Pulmonary function abnormalities were detected in 46.43 % (65 out of 140) of patients, primarily manifesting as diffusion dysfunction (26.43 %), followed by ventilatory dysfunction (5.0 %), and mixed pulmonary dysfunction (15.0 %). A serum ferritin level above 2500 ng/ml significantly correlated with the occurrence of these abnormalities(OR = 3.187, 95%CI:1.312-7.741, P = 0.010), while higher hemoglobin concentrations demonstrated a protective effect (OR = 0.966, 95%CI: 0.943-0.989, P = 0.004). Our study highlights diffusion dysfunction as the most prevalent type of pulmonary function abnormalities in TDT patients. Furthermore, it establishes a correlation between elevated serum ferritin levels and pulmonary dysfunction.
    Keywords:  Iron overload; Pulmonary function; Serum ferritin; Transfusion-dependent thalassemia
    DOI:  https://doi.org/10.1016/j.heliyon.2024.e38069
  5. Haematologica. 2024 Oct 17.
    Lysine succinylation precisely controls normal erythropoiesis.
    Bin Hu, Han Gong, Ling Nie, Ji Zhang, Yanan Li, Dandan Liu, Huifang Zhang, Haihang Zhang, Lu Han, Chaoying Yang, Maohua Li, Wenwen Xu, Yukio Nakamura, Lihong Shi, Mao Ye, Christopher D Hillyer, Narla Mohandas, Long Liang, Yue Sheng, Jing Liu.
      Lysine succinylation (Ksu) has recently emerged as a protein modification that regulates diverse functions in various biological processes. However, the systemically and precise role of lysine succinylation in erythropoiesis remains to be fully elucidated. In this study, we noted a prominent increase of succinyl-CoA and lysine succinylation during human erythroid differentiation. To explore the functional significance of succinylation, we inhibited succinylation by either knock downing key succinyltransferases or overexpressing desuccinylases. Succinylation inhibition led to suppressed cell proliferation, increased apoptosis, and disrupted erythroid differentiation. In vivo overexpression of the desuccinylases SIRT5 delayed erythroid differentiation. Furthermore, integrative proteome and succinylome analysis identifies 939 succinylated proteins with 3,562 Ksu sites, distributed across various cellular compartments and involved in multiple cellular processes. Significantly, inconsistencies between protein expression levels and succinylation levels were observed, indicating that the succinylation of certain proteins may function independently of expression. Mechanistically, we implicated KAT2A-mediated succinylation of histone H3 K79, leading to chromatin remodeling and subsequently erythropoiesis regulation. Specially, we identified CYCS as a key regulator of erythropoiesis, which depends on its succinylation sites K28/K40. Taken together, our comprehensive investigation of the succinylation landscape during erythropoiesis provides valuable insights into its regulatory role and offer potential implications for erythroid-related diseases.
    DOI:  https://doi.org/10.3324/haematol.2024.285752
  6. Hemoglobin. 2024 Oct 14. 1-4
    δβ-Thalassemia and α-Triplication: Is Genetic Retesting Worthwhile in Case of Non-Coherent Phenotype?
    Cristina Giubbilei, Simona D'Angelo, Ilaria Fotzi, Massimo Mogni, Paola Guglielmelli, Alessandro Maria Vannucchi, Valentina Carrai.
      Thalassemia is a heterogenous group of hemoglobinopathies; intermediate thalassemia's phenotype can be very variegated due to different genetic matching. Before NGS-era, diagnosis often mismatched with phenotypes, hiding some genetic findings that nowadays could completely explain clinical presentation. In this report, we emphasize the importance of reevaluating genetic testing to achieve a correct diagnosis in case of phenotype mismatch thalassemia. Starting from a suspect of δ/β thalassemia heterozygosity, reevaluating revealed heterozygosity for α-gene triplication combined to δ and β heterozygosity, a new finding that completely suited patient's clinical manifestation. This case provided the opportunity to underline that an extended study on total globin genes is essential for correct diagnosis of thalassemia, especially when clinical onset phenotypes are more divisive and questionable at a first clinical work-up.
    Keywords:  genetic retesting; intermediate-thalassemia; α-triplication; β-thalassemia; δ-thalassemia
    DOI:  https://doi.org/10.1080/03630269.2024.2414109
  7. J Cell Sci. 2024 Oct 01. pii: jcs261673. [Epub ahead of print]137(19):
    Erythroblast enucleation at a glance.
    Lucas M Newton, Velia M Fowler, Patrick O Humbert.
      Erythroid enucleation, the penultimate step in mammalian erythroid terminal differentiation, is a unique cellular process by which red blood cells (erythrocytes) remove their nucleus and accompanying nuclear material. This complex, multi-stage event begins with chromatin compaction and cell cycle arrest and ends with generation of two daughter cells: a pyrenocyte, which contains the expelled nucleus, and an anucleate reticulocyte, which matures into an erythrocyte. Although enucleation has been compared to asymmetric cell division (ACD), many mechanistic hallmarks of ACD appear to be absent. Instead, enucleation appears to rely on mechanisms borrowed from cell migration, endosomal trafficking and apoptosis, as well as unique cellular interactions within the microenvironment. In this Cell Science at a Glance article and the accompanying poster, we summarise current insights into the morphological features and genetic drivers regulating the key intracellular events that culminate in erythroid enucleation and engulfment of pyrenocytes by macrophages within the bone marrow microenvironment.
    Keywords:  Enucleation; Erythroblastic islands; Erythropoiesis
    DOI:  https://doi.org/10.1242/jcs.261673
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