bims-conane 2024-12-29 papers

Metabolites. 2024 Dec 20. pii: 717. [Epub ahead of print]14(12):

Reproductive Health in Women with Major β-Thalassemia: Evaluating Ovarian Reserve and Endocrine Complications.

Vasileios Tsilionis, Efthalia Moustakli, Stefanos Dafopoulos, Athanasios Zikopoulos, Sotirios Sotiriou, Athanasios Zachariou, Konstantinos Dafopoulos.

Thalassemia is an autosomal recessive hereditary chronic hemolytic anemia characterized by a partial or complete deficiency in the synthesis of alpha- or beta-globin chains, which are essential components of adult hemoglobin. Mutations in the globin genes lead to the production of unstable globin chains that precipitate within cells, causing hemolysis. This shortens the lifespan of mature red blood cells (RBCs) and results in the premature destruction of RBC precursors in the bone marrow. Regular red blood cell transfusions are the standard treatment for thalassemia. However, these transfusions can lead to increased iron overload, which can impair vital systems such as the liver, heart, ovaries, and endocrine system. Focusing on female reproductive endocrinology, recurrent blood transfusions can cause iron accumulation in the pituitary and hypothalamus, leading to hypogonadotropic hypogonadism (HH), the most common endocrinopathy in these patients, affecting 40-91% of women. Recurrent transfusions and the resulting iron overload can also lead to oxidative stress and ovarian damage in patients with beta-thalassemia major (BTM). Despite advancements in iron chelation therapy, hypothalamic-pituitary damage associated with HH contributes to subfertility and sexual dysfunction, often with little to no recovery. In women exposed to gonadotoxic drugs, particularly those with BTM, anti-Mullerian hormone (AMH)-a marker of ovarian reserve-is frequently used to assess ovarian damage. This review aims to explore the pathophysiology of β-thalassemia and its major clinical manifestations, with a focus on endocrine complications and their impact on ovarian reserve. It also investigates how metabolomics can provide insights into the disease's metabolic alterations and inform current and emerging therapeutic strategies to mitigate complications and optimize patient outcomes, potentially leading to more effective and personalized treatments.

Keywords: HPG axis; hemoglobinopathies; infertility; ovarian biomarkers; reproductive endocrinology; reproductive health

DOI: https://doi.org/10.3390/metabo14120717

Int J Lab Hematol. 2024 Dec 27.

Molecular Characterization of δβ Thalassemia/Hereditary Persistence of Fetal Hemoglobin and Its Correlation With Clinical and Hematological Profile; a Single Center Study in North India.

R Gupta, A Shah, K Gupta, D Chandra, A Sharma, K Rahman, M K Singh, S Yadav, R Kashyap.

BACKGROUND: δβ-thalassemia/HPFH is an uncommon hemoglobinopathy characterized by decreased or the total absence of production of δ- and β-globin and increased HbF levels. Both these disorders have variable genotype and phenotype, but significant overlap in the clinical and laboratory findings. Given the lack of literature in this regard, the study aimed to estimate the prevalence of the disease and evaluate its clinical, hematological, and molecular profile in India.
MATERIAL AND METHODS: This was a retrospective study where all samples with HbF level ≥ 5% and suspected to be δβ-thalassemia/HPFH, based on the HPLC, were included in the study over 3.5 years. The demographic and clinical details were retrieved from the electronic medical records. Gap-PCR was carried out to characterize the molecular defect for the HbF determinant, while amplification refractory mutation system (ARMS-PCR) was carried out for β-thalassemia genoyping. Clinical and laboratory parameters of heterozygous and homozygous/compound heterozygous δβ thalassemia deletions were compared.
RESULTS: A total of 65 individuals (0.8%) were diagnosed with δβ-thalassemia/HPFH; these included 45 (69%) patients in the heterozygous group and 20 (31%) cases in the homozygous/compound heterozygous subgroup. While all the carrier states were asymptomatic, 80% of the patients in the homozygous/compound heterozygous state were symptomatic with a thalassemia intermedia-like profile. The median Hb levels were 12.3 g/dL (range -9.5-18.2) and 8.0 g/dL (range 3.8-15.1) respectively. Molecular profiling identified heterozygous Asian Indian inversion deletion Gγ(Aγδβ)0 mutation in 50% of cases, heterozygous HPFH-3 (Indian HPFH, 48.5 kb deletion) in 14% cases, and homozygous Gγ(Aγδβ)0-thalassemia in 21% cases. Compound heterozygous HPFH-3/Gγ(Aγδβ)0 mutation with β-thalassemia was observed in 8.9% and 3.5%, respectively. In one case, the HbF determinant could not be identified. Heterozygous (HBB:c. 92+5G>C), was the most frequent co-inherited β-thalassemia mutation in the compound heterozygous patients.
CONCLUSION: The study highlights that high HbF determinants, like δβ thalassemia and HPFH, are relatively more frequent in the Indian subcontinent, and their co-inheritance with β-thalassemia results in a moderately severe disease. Accurate identification of molecular defects is important for prenatal diagnosis and genetic counseling.

Keywords: India; delta‐beta thalassemia; hereditary persistence of fetal hemoglobin (HPFH); molecular

DOI: https://doi.org/10.1111/ijlh.14419

J Biol Chem. 2024 Dec 21. pii: S0021-9258(24)02621-8. [Epub ahead of print] 108119

ID3 promotes erythroid differentiation and is repressed by a TAL1/PRMT6 complex.

Vivien Heller, Lei Wang, Edith Schneider, Mirjam Gerstner, Luana Bajer, Robin Decker, Halvard Boenig, Joern Lausen.

Erythropoiesis is controlled by transcription factors that recruit epigenetic cofactors to establish and maintain erythrocyte-specific gene expression patterns while repressing alternative lineage commitment. The transcription factor TAL1 is critical for establishing erythroid gene expression. It acts as an activator or repressor of genes, depending on associated epigenetic cofactors. Understanding the epigenetic function of TAL1 during erythropoiesis is key to improving in vitro erythroid differentiation and understanding pathological erythropoiesis. Therefore, the regulatory mechanisms that control the function of TAL1 during erythropoiesis are under intense investigation. Here we show that TAL1 interacts with PRMT6 on the ID3 gene in K562 and hCD34+ cells. The ID protein family is a critical transcriptional regulator of hematopoietic cell differentiation. We show that TAL1 and PRMT6 are present at the ID3 promoter, and that TAL1 is involved in the recruitment of PRMT6. Here, PRMT6 epigenetically regulates ID3 expression by mediating H3R2me2a. Thus, TAL1/PRMT6 epigenetically represses ID3 expression in progenitors, which is relieved upon erythroid differentiation, leading to increased ID3 expression. Overexpression of ID3 in primary hCD34+ cells enhances erythropoiesis. Our results show that a TAL1/PRMT6 complex regulates genes important for erythropoiesis, such as ID3. Manipulation of ID3 expression may be a way to promote in vitro differentiation of hCD34+ cells into erythrocytes.

DOI: https://doi.org/10.1016/j.jbc.2024.108119

Stem Cell Res Ther. 2024 Dec 21. 15(1): 495

A novel conditioning regimen with pre-transplantation immunosuppression reduces the complication rates in hematopoietic stem cell transplantation in transfusion-dependent β-thalassemia.

Huaqing Yang, Xinyu Li, Liping Que, Han Chen, Liping Zhan, Dunhua Zhou, Yang Li, Shaofen Lin, Yin Wang, Xiaojun Wu, Xiawei Han, Zhengzhou Wu, Danping Zhong, Ke Huang, Honggui Xu, Jianpei Fang.

BACKGROUND: Allo-HSCT is a curative therapy for patients with transfusion-dependent thalassemia (TDT). The high incidence of transplant-related complications is becoming an obstacle to safe and effective unrelated donor (URD) transplantation.
METHODS: In this retrospective study, we reported the survival outcomes and complications of transplantation in thalassemia patients using a novel regimen consisting of pre-transplantation immunosuppression (PTIS) and modified myeloablative conditioning based on intravenous busulfan, cyclophosphamide, fludarabine, and rabbit anti-human thymocyte immunoglobulin.
RESULTS: A total of 88 thalassemia patients received the novel conditioning regimen (NCR group), while 118 patients received the conventional conditioning regimen (CCR group). The median age at HSCT in the NCR group was older (7 years vs. 4 years, p < 0.05). No patient in the NCR group experienced primary graft failure, while the 3-year probabilities of OS and TFS were 96.6% and 93.2%, respectively. Even when the intensity of conditioning was reduced, OS (94.8% vs. 94.3%, p = 0.848) and TFS (89.8% vs. 92.5%, p = 0.663) in URD transplants in the NCR group were comparable to those in the CCR group, while the risk of autoimmune hemolytic anemia (AIHA) (0% vs. 15.1%) was lower. In addition, the NCR group had lower rates of mixed chimerism (7.1%).
CONCLUSIONS: URD transplantation can achieve a comparable prognosis to matched sibling donor (MSD) transplantation with a lower incidence of AIHA due to PTIS and modified myeloablative conditioning regimen.

Keywords: children; hematopoietic stem cell transplantation; pre-transplantation immunosuppression; transfusion-dependent β-thalassemia; unrelated donor transplantation

DOI: https://doi.org/10.1186/s13287-024-04103-6