bims-conane 2025-11-09 papers

Trends Cell Biol. 2025 Nov 03. pii: S0962-8924(25)00224-7. [Epub ahead of print]

Understanding and targeting erythroid cell metabolism.

Min Ni, Natalia Scaramellini, Irene Motta, Jian Xu.

Red blood cell (RBC) production, or erythropoiesis, serves as a paradigm for studying cellular differentiation in both physiological and pathological contexts. While the transcriptional and epigenetic programs controlling erythropoiesis are well characterized, the metabolic regulation of this complex process remains underexplored. Recent discoveries that pyruvate kinase activators improve outcomes in sickle cell disease and thalassemia underscore the therapeutic potential of targeting metabolism in RBC disorders. However, further progress is limited by an incomplete understanding of the metabolic networks supporting erythropoiesis and RBC function. This review highlights emerging insights into erythroid metabolic reprogramming involving bioenergetic and biosynthetic processes, newly discovered pathways shaping the erythroid metabolome, and the promise and challenges of exploiting metabolic vulnerabilities in inherited and acquired red cell disorders.

Keywords: erythropoiesis; metabolism; metabolism-directed therapy; sickle cell disease; thalassemia

DOI: https://doi.org/10.1016/j.tcb.2025.10.001

Blood. 2025 Nov 05. pii: blood.2025030211. [Epub ahead of print]

Silencing of BCL11A by Disrupting Enhancer-Dependent Epigenetic Insulation.

Kaili Wang, Juan Wang, Ruopeng Feng, Kseniia Dudnyk, Yoon Jung Jung Kim, Jun Yi Stanley Lim, Michael Lee, Yuannyu Zhang, Xiaofei Gao, Yong Cheng, Stuart Orkin, Jian Zhou, Mitchell J Weiss, Feng Yue, Jian Xu.

The transcription factor BCL11A is a genetically and clinically validated regulator of the fetal-to-adult hemoglobin switch in human erythroid cells. CRISPR editing of an intronic enhancer within the BCL11A gene reactivates fetal hemoglobin (HbF) in adult erythroid cells, serving as the first CRISPR-based therapy for β-hemoglobinopathies. However, the molecular basis for the remarkable efficacy of CRISPR-mediated enhancer ablation remains elusive. Here, we describe a new genome architecture, an enhancer-dependent chromatin rosette, that is essential for epigenetic insulation and the developmentally regulated, hematopoietic lineage-specific expression of BCL11A. CRISPR-mediated disruption of the BCL11A erythroid enhancer impairs transcription of enhancer-driven RNAs and NIPBL-dependent cohesin loading, leading to destabilization of the rosette structure, loss of chromatin insulation, and epigenetic silencing of BCL11A. Moreover, targeted depletion enhancer RNAs using antisense oligonucleotide silences BCL11A by disrupting epigenetic insulation, causing HbF reactivation in adult erythroid cells. These findings uncover an essential role for enhancer-driven epigenetic insulation in transcriptional control, presenting a new strategy for therapeutic targeting of BCL11A.

DOI: https://doi.org/10.1182/blood.2025030211

Front Oncol. 2025 ;15 1665179

Hereditary spherocytosis concomitant with JAK2V617F-positive primary myelofibrosis: a case report.

Chi-E Qiu, Lei Lei, Guosong Jiang, Xiuqun Huang, Yadan Li.

Hereditary spherocytosis (HS) is a genetic hemolytic disorder primarily characterized by hemolytic anemia, jaundice, splenomegaly, and frequent complications, including cholelithiasis, accompanied by the presence of spherocytes in the peripheral blood. This disorder predominantly follows an autosomal dominant inheritance pattern; however, certain cases exhibit an autosomal recessive mode of inheritance. HS is the most prevalent disorder associated with defects in the red blood cell membrane. Primary myelofibrosis (PMF), a chronic myeloproliferative neoplasm (MPN) characterized by splenomegaly resulting from extramedullary hematopoiesis, is associated with the JAK2 V617F mutation. Currently, there are no documented instances of co-occurrence of HS and PMF in the literature. We report the case of a 37-year-old male who experienced recurrent abdominal distension and splenomegaly over the past decade, along with elevated platelet counts over the past nine years. The patient tested positive for the JAK2V617F mutation, and bone marrow smears revealed the presence of teardrop-shaped erythrocytes. Peripheral blood smears indicated the presence of approximately 20% of spherocytes. The morphology of the bone marrow biopsy specimen was consistent with an MPN, classified as MF-2 grade. The highly specific eosin-5'-maleimide binding assay demonstrated a reduced mean fluorescence intensity of 25.73%. The patient was managed with aspirin and ruxolitinib and continued to be monitored through follow-up evaluations.

Keywords: JAK2V617F; comorbidity; hereditary spherocytosis; myeloproliferative neoplasm; primary myelofibrosis

DOI: https://doi.org/10.3389/fonc.2025.1665179

Cytotherapy. 2025 Oct 01. pii: S1465-3249(25)00849-7. [Epub ahead of print] 101989

María Isabel Benítez-Carabante, Angela Menárguez López, María Luz Uría Oficialdegui, Cristina Beléndez Bieler, Melissa Panesso Romero, Mercedes Plaza Fornieles, Carolina Fuentes, Sara Vinagre Enríquez, Graciela Gómez Silva, Mónica López Duarte, José María Pérez Hurtado, Montserrat Torrent, Laura Alonso García, Cristina Diaz-de-Heredia.

INTRODUCTION: Patients with transfusion-dependent b-thalassaemia (TDT) suffer from severe anemia, both primary and secondary iron overload and end-organ damage. Although new disease-modifying and curative therapies are emerging, hematopoietic stem cell transplantation (HSCT) remains the most widely available curative option for TDT patients. This study aims to compare HSCT outcomes according to the type of donor used, considering not only survival, but also graft-versus-host disease (GVHD) and other transplant-related complications.
METHODS: A multicentre retrospective study was conducted, in which children who received a first HSCT for TDT were included.
RESULTS: Fifty-eight patients were included, with a median follow-up of 7.4 years. The median age at HSCT was 5.6 years (range 0.76-16.64). Thirty-nine patients received a matched family donor (MFD) transplant, and 19 received an unrelated donor transplant of whom 16 received a fully matched unrelated donor (MUD) and 3 a mismatched unrelated donor cord blood (CB) transplant. Most patients received bone marrow alone or in combination with CB (n = 49); six patients received CB, and 3 patients' peripheral blood. Thirty-six patients received busulfan, while the remaining patients received a treosulfan-based conditioning regimen. The incidence of grade II-IV acute GVHD was significantly higher in the MUD group than in the MFD group (56.25% vs. 25.71%, P = 0.0178). No significant differences were found in grade III-IV acute GVHD or chronic GVHD. Although the incidence of endothelial complications was higher in patients receiving an MUD transplant, it was not statistically significant. With 2-year overall survival (OS), thalassaemia free survival (TFS) and chronic GVHD thalassaemia-free survival of 98%, 92.2% and 82.7%, respectively, there were no differences between the MFD and MUD groups.
CONCLUSION: Fully matched unrelated donor transplantation may offer a real curative opportunity for pediatric patients with TDT who lack an MSD, with excellent OS, TFS and low incidence of grade III-IV acute and chronic GVHD. Future research into the prevention and treatment of GVHD will further improve these results.

Keywords: children; hematopoietic stem cell transplantation; transfusion-dependent thalassaemia; unrelated donor

DOI: https://doi.org/10.1016/j.jcyt.2025.09.012

Lancet Haematol. 2025 Nov;pii: S2352-3026(25)00286-8. [Epub ahead of print]12(11): e857-e859

Incorporating national disease burden in GBD estimates of haemoglobinopathies in Italy.

Italian Haemoglobinopathies National Survey Group

DOI: https://doi.org/10.1016/S2352-3026(25)00286-8