Blood advances最新文献

{"title":"Phase I Study of Rogocekib in Patients with Relapsed or Refractory Hematologic Malignancies.","authors":"Hisayuki Yokoyama, Noriko Fukuhara, Koji Ando, Hiroatsu Iida, Takahiro Yamauchi, Suguru Fukuhara, Koji Izutsu, Yasushi Tanoue, Maki Yamamoto, Hirokazu Tozaki, Eiji Takahara, Shingo Shoji, Akio Mizutani, Daisuke Morishita, Robert Westley Oda, Hiroshi Miyake, Noboru Yamamoto","doi":"10.1182/bloodadvances.2025017601","DOIUrl":"https://doi.org/10.1182/bloodadvances.2025017601","url":null,"abstract":"<p><p>Rogocekib (development name CTX-712) is a first-in-class, orally available, highly potent, and selective small molecule inhibitor of CDC2-like kinase (CLK), a key regulator of the RNA splicing process. Preclinical studies demonstrated anti-proliferative activity on various in-vitro and in-vivo models of hematologic malignancies. Based on these findings, a phase I study of rogocekib was conducted to evaluate the safety and preliminary efficacy in patients with relapsed or refractory acute myeloid leukemia (AML) and higher-risk myelodysplastic syndrome (MDS). Using a 3+3 design informed by prior solid tumor safety data, patients received 70 mg or 105 mg twice a week (TW) in capsule form. One dose limiting toxicity (DLT) of Grade 4 Pneumonia was observed in the 105 mg TW cohort. Among 12 AML patients, complete remission (CR) was observed in 3 patients (25.0%), and CR with incomplete hematologic recovery (CRi) was observed in 1 patient (8.3%). In MDS patients (n=2), CR was observed in 1 patient (50.0%). Pharmacokinetics (PK) analyses showed higher mean Cmax and AUC0-24 of rogocekib at 105 mg compared to 70 mg. Pharmacodynamics (PD) analysis showed that the relative magnitude of exon skipping in peripheral blood cells increased with exposure of rogocekib. Rogocekib demonstrated a manageable and tolerable safety profile in patients with hematologic malignancies. This study was registered on the Japan Registry of Clinical Trials under jRCT2080224127. Currently, a Phase I/II Study of rogocekib in relapsed/refractory AML and higher risk MDS is ongoing in the United States (NCT05732103).</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145243654","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MicroRNA-223-3p is a determinant of platelet procoagulant activity.","authors":"Julia Charlon-Gay, Séverine Nolli, Sylvie Dunoyer-Geindre, Paulina Ciepla, Jean-Luc Reny, Pierre Fontana","doi":"10.1182/bloodadvances.2024015290","DOIUrl":"https://doi.org/10.1182/bloodadvances.2024015290","url":null,"abstract":"<p><p>MicroRNAs (miRNAs) are regulators of platelet function and may thus contribute to inter-individual variability in platelet reactivity. MiR-223-3p is the most abundant of the platelet-derived miRNAs. Several studies have reported an association between miR-223-3p levels and platelet reactivity or the recurrence of cardiovascular events, but this miRNA's impact on platelet function is still poorly understood. We aimed to investigate miR-223-3p's effects on platelet reactivity in platelets derived from human hematopoietic stem cells (CD34+) and to study the underlying mechanisms of its action. MiR-223-3p upregulation and downregulation were carried out by transfecting megakaryocytes (MKs) derived from CD34+ cells with a miR-223-3p mimic or Cas9/sgRNAs ribonucleoprotein complexes, respectively. Flow cytometry was used to quantify the expression of surface markers of MKs and platelets, platelet production, and platelet reactivity. Platelet-supported thrombin generation was quantified in human plasma. Downregulation of miR-223-3p resulted in fewer proplatelet swellings and decreased platelet production. MiR-223-3p upregulation and downregulation affected the proportion of procoagulant platelets. This phenotype was mirrored by changes in the gene expression of the transmembrane protein 16F (TMEM16F), a phospholipid scramblase that plays a key role in the generation of procoagulant platelets. A luciferase reporter gene assay validated that TMEM16F mRNA was a direct target of miR-223-3p. Platelet-supported thrombin generation was reduced when miR-223-3p was upregulated. In conclusion, miR-223-3p modulates the generation of procoagulant platelets.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145243702","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ablation of CD38 in Multiple Myeloma Cells Leads to an Aggressive Phenotype in a Mouse Xenograft Model.","authors":"Michael Riley Dyer, Alexander Zheleznyak, Erin N Teubner, Julie Prior, Brad Manion, Zhenghan Jing, Amit K Sharma, Junwei Du, Rui Tang, Mark A Fiala, John F DiPersio, Deborah Veis, Julie O'Neal, Mikhail Y Berezin, Monica Shokeen","doi":"10.1182/bloodadvances.2025017296","DOIUrl":"https://doi.org/10.1182/bloodadvances.2025017296","url":null,"abstract":"<p><p>Multiple myeloma (MM) is a plasma cell malignancy characterized by bone pain and organ failure. A major challenge in treating MM is therapeutic resistance. CD38-targeted immunotherapies, such as daratumumab, have significantly improved outcomes, however, variable responses, resistance, and relapse remain challenges. We hypothesized that loss of CD38 drives a more aggressive phenotype and resistance to therapy. To test this, we developed a CD38 knockout (KO) clone of a human MM cell line and evaluated it in immunodeficient mice. Mice with CD38 KO tumors exhibited an increased tumor burden and reduced survival compared to those with CD38 WT tumors. Imaging and histology revealed increased osteolytic lesions caused by CD38 KO tumors, while FDG PET demonstrated elevated metabolic activity and tracer uptake in KO tumors. Mice with CD38 KO tumors also developed bilateral kidney metastases, whereas none occurred in WT tumors. Blood analysis showed elevated markers of disease progression and renal dysfunction, and cytokine profiling identified increased pro-inflammatory cytokines within the bone microenvironment. RNA-seq identified marked transcriptional changes, with enrichment of pathways involving cell adhesion, cytokine signaling, and migration. Daratumumab-resistant MM.1S cells mirrored CD38 KO cells with reduced cell cycle progression and dexamethasone sensitivity, underscoring the microenvironment's role in driving aggressiveness and implicating CD38 loss as a possible mediator of cross-resistance. Overall, these findings demonstrate that CD38 loss drives an aggressive MM phenotype characterized by bone degradation, renal metastasis, and reduced survival, highlighting the need to develop strategies to target CD38-deficient clones and offering RNA signatures as candidate regulators of this phenotype.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145243656","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Challenges and Opportunities for Improvement in the Practical Management of Adults with Acute Lymphoblastic Leukemia.","authors":"Ryan D Cassaday","doi":"10.1182/bloodadvances.2025017584","DOIUrl":"https://doi.org/10.1182/bloodadvances.2025017584","url":null,"abstract":"<p><p>As our approaches to the management of adults with acute lymphoblastic leukemia (ALL) have become more effective, they have introduced new administrative complexities. These include challenges pertaining to medication administration and financial implications of treatment choices. And since approximately half of these patients are typically treated outside of larger referral centers, these difficulties are being passed on to clinicians in settings that rarely encounter this complex disease. Instead of an evidence-focused review on contemporary management of ALL in adults, this article seeks to highlight how some of these important medical advances may be difficult to operationalize outside of high-volume centers. It will also attempt to identify areas where clinicians and investigators might consider modifying their respective approaches to mitigate how the realities of modern medical care may impact our ability to optimally manage these patients now and in the future.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145243687","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Myeloproliferative neoplasm subtypes have distinct impact on risk of incident osteoporosis and osteoporotic fractures.","authors":"Michelle H Lee, Yating Wang, Angel M Cronin, Angela C Tramontano, Lachelle D Weeks, Gabriela S Hobbs","doi":"10.1182/bloodadvances.2025017168","DOIUrl":"https://doi.org/10.1182/bloodadvances.2025017168","url":null,"abstract":"<p><p>NA (revised as letter).</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145243708","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Risk stratification of diffuse large B-cell lymphoma patients using plasma NMR-based metabolomics at diagnostic.","authors":"Aurélie Montagne, Gildas Bertho, Thomas Papastergiou, Loïc Chartier, Romain Ricci, Fabrice Jardin, Herve Ghesquieres, Cédric Rossi, Franck Morschhauser, Corinne Haioun, Vincent Ribrag, Pierre Feugier, Gabriel Brisou, Lucie Obéric, Philippe Gaulard, Nicolas Giraud, Younès Bennani, Catherine Thieblemont, Véronique I Baud","doi":"10.1182/bloodadvances.2025017248","DOIUrl":"https://doi.org/10.1182/bloodadvances.2025017248","url":null,"abstract":"<p><p>Early detection of ultra-risk diffuse large B-cell lymphoma (DLBCL) is an unmet medical need to aid patient stratification for alternative treatment approaches. Metabolomics applied to cancer patient biofluids has emerged as a novel Omics that could provide important information to better stratify cancer patients. We performed a retrospective study by nuclear magnetic resonance (NMR)-based metabolomics using plasma samples at diagnosis from 154 randomized DLBCL patients treated by R-CHOP (from the phase 3 REMARC trial, #NCT01122472). Remarkably, we identified a combination of three circulating metabolites linked to lipid metabolism (named the \"NMR score\") that significantly impacted on overall survival (OS) (p < 0.0001) and progression-free survival (PFS) (p = 0.0003). The optimal cut off for each metabolite was determined using X-Tile and confirmed by a training validation method. Combining 2-amino-butyrate, 3-hydroxy-butyrate and LDL-1 lipoprotein yielded three risk groups with low (0-1), intermediate (2-3) and high risk (4-5) patients. GCB/non-GCB profile along with Bcl2 and Myc expression did not correlate with NMR score survival. In conclusion, we revealed that a combination of three circulating metabolites linked to lipid metabolism is a feature that capture DLBCL patient heterogeneity. This NMR score appeared promising for DLBCL risk stratification, even among responder patients after R-CHOP treatment.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145243742","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Germline LCP1 mutations cause immunodeficiency with neutropenia, monocytopenia, lymphopenia and defective cytokinesis.","authors":"Thijs van Bergen, Dennis Bosch, Christine Bellanné-Chantelot, Roger Mulet-Lazaro, Jacob R Bledsoe, Lanpeng Chen, Hans W J de Looper, Claire van Dijk, Mariëtte Ter Borg, Eric Bindels, Remco Hoogenboezem, Onno Roovers, Patricia A Olofsen, Marije Bartels, Joris M van Montfrans, Puck Breed, Elisabeth Salzer, Marloes G Holierhoek, Brigittie Nelken, Blandine Beaupain, Mark Daniel Fleming, Akiko Shimamura, Marc H G P Raaijmakers, Jean Donadieu, Peter E Newburger, Ivo P Touw, Anna M Aalbers","doi":"10.1182/bloodadvances.2025016507","DOIUrl":"https://doi.org/10.1182/bloodadvances.2025016507","url":null,"abstract":"<p><p>Severe congenital neutropenia (SCN) is characterized by neutropenia, recurrent infections and an increased leukemia risk. Multiple genetic defects underlying SCN have been identified, but a genetic diagnosis is still lacking in a significant proportion of patients. Here, we report four independent pedigrees with heterozygous variants in LCP1. Variants c.740-1G>T and c.740-20_744del resulted in the same alternatively spliced RNA product, causing an in-frame deletion (p.A247_E254del). Variant c.509C>T in the third pedigree resulted in p.S170L, and variant c.806T>C in the fourth pedigree in p.L269P. Affected individuals suffer from neutropenia, poor or complete lack of response to G-CSF treatment, and variable degrees of lymphopenia, hypogammaglobulinemia, and monocytopenia. Patients with A247_E254del and p.L269P presented with tetraploid cells in the bone marrow, indicative of disturbed cytokinesis. In one of these kindreds, two individuals developed acute leukemia. G-CSF non-responsiveness and defective cell cycling were repaired upon correction of the LCP1 A247_E254del variant in patient-derived induced pluripotent stem cells, supporting the monogenic origin of the disease. Indicative of their gain-of-function, both A247_E254del and S170L variants increased F-actin bundling and formation of abnormal protrusions. Single-cell transcriptome analysis of A247_E254del bone marrow-derived hematopoietic stem and progenitor cells (HSPCs) showed deregulation of signaling pathways controlling mitosis in multi-lineage and lymphoid-primed HSPC subsets. We conclude that activating LCP1 variants cause a new hematopoietic disorder with autosomal dominant inheritance. Depending on the consequences of the LCP1 variants for protein structure, patients may suffer from G-CSF refractory severe neutropenia, lymphopenia, hypogammaglobulinemia, monocytopenia, and defective cytokinesis.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145243650","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FLT3-ITD measurable residual disease from the QuANTUM-First trial.","authors":"Mark J Levis, Harry P Erba, Pau Montesinos, Hee-Je Kim, Radovan Vrhovac, Elzbieta Patkowska, Pavel Zak, Po-Nan Wang, Jaime E Connolly Rohrbach, Ken Chang, Li Liu, Yasser Mostafa Kamel, Karima Imadalou, Arnaud Lesegretain, Jorge E Cortes, Mikkael A Sekeres, Hervé Dombret, Sergio Amadori, Jianxiang Wang, Richard F Schlenk, Alexander E Perl","doi":"10.1182/bloodadvances.2025016444","DOIUrl":"https://doi.org/10.1182/bloodadvances.2025016444","url":null,"abstract":"<p><p>QuANTUM-First was a randomized trial that demonstrated that the addition of quizartinib, a potent and selective FLT3 inhibitor, to induction and consolidation chemotherapy, followed by monotherapy maintenance, improved the survival for patients with newly diagnosed FLT3-ITD (FMS-like tyrosine kinase 3‒internal tandem duplication)--mutated acute myeloid leukemia (AML). We conducted a post-hoc analysis of the trial data focusing on measurable residual disease (MRD) as assayed using an amplicon-based next-generation sequencing assay and on the impact of molecular biomarkers such as FLT3-ITD insertion length and co-mutations. This is the first prospective, randomized trial of a FLT3 inhibitor in newly diagnosed patients in which FLT3-ITD MRD data were collected throughout therapy. We established that quizartinib induces deeper remissions with respect to FLT3-ITD MRD vs placebo, and that the amount of MRD at the completion of induction correlates with relapse and survival. We found that longer FLT3-ITD insertion mutations correlated with worse outcome, quizartinib was beneficial irrespective of insertion mutation length, and the FLT3-ITD MRD assay was more sensitive when bone marrow was used vs peripheral blood. Regardless of the presence of NPM1 co-mutation, quizartinib increased the rates of MRD-negative patients at the end of induction vs placebo. Finally, comparison of the FLT3-ITD mutation length between the polymerase chain reaction (PCR) with capillary electrophoresis assay obtained at screening and the PCR next-generation sequencing MRD assay performed at the end of induction showed a 96.2% concordance with the exact ITD length. This trial was registered at www.ClinicalTrials.gov as NCT02668653.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145237873","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Matched Unrelated vs Haploidentical Donor Hematopoietic Cell Transplantation Using Post-Transplant Cyclophosphamide.","authors":"Dipenkumar Modi, Yosra M Aljawai, Todd E DeFor, Caitrin Bupp, Monzr M Al Malki, Javier Bolaños-Meade, Mahasweta Gooptu, Antonio M Jimenez Jimenez, Hongtao Liu, Felix Mensah, Marco Mielcarek, Brian C Shaffer, Bronwen E Shaw, Stephen R Spellman, Heather E Stefanski, Jeffery J Auletta, Steven M Devine, Farhad Khimani, Ramzi Abboud","doi":"10.1182/bloodadvances.2025017194","DOIUrl":"https://doi.org/10.1182/bloodadvances.2025017194","url":null,"abstract":"<p><p>Post-transplant cyclophosphamide (PTCy)-based graft-vs-host disease (GVHD) prophylaxis is the new standard for matched unrelated donor (MUD) hematopoietic cell transplantation (HCT). Prior studies comparing MUD and haploidentical donor HCT using PTCy were limited by size and short follow-up. We therefore performed a registry-based analysis examining the impact of donor type on HCT with PTCy. Adult patients (n=5,873) who received MUD (n=1,973) or haploidentical (n=3900) HCT with PTCy for acute leukemia (74.2%) or myelodysplastic syndrome (25.8%) reported to the CIBMTR between 2017- 2021 were included. Primary endpoints were three-year overall survival (OS) and GVHD-free, relapse-free survival (GRFS). Cox regression and sensitivity analyses were performed through adjustment of propensity scores. Haploidentical HCT had worse OS (Hazard ratio [HR] 1.15, 95% confidence interval [CI] 1.04-1.27, p=0.005) and GRFS (HR 1.19, 95% CI 1.10-1.29, p<0.001) compared to MUD HCT. Donor age was the only other consistent donor-related factor associated with survival. Results were confirmed in a sensitivity analysis adjusted for propensity scores. When the cohort was restricted to reduced intensity conditioning only or donors <30 years-old, OS did not differ between groups. Haploidentical HCT was associated with higher primary graft failure (HR 1.67; p=0.002), increased grade III-IV acute GVHD (HR 1.28; p=0.039), higher moderate/severe chronic GVHD (HR 1.47; p<0.001) and non-relapse mortality (HR 1.34; p<0.001). Grade II-IV aGVHD and relapse risk did not differ between the donor types. This large analysis showed that in adults with acute leukemia or MDS, MUD HCT was associated with improved outcomes compared to haplo HCT with PTCy-based GVHD prophylaxis.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145237913","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel isoform of Tensin1 promotes actin filament assembly for efficient erythroblast enucleation.","authors":"Arit Ghosh, Megan Coffin, Dimitri M Diaz, Sarah Barndt, Vincent Schulz, Patrick G Gallagher, Su Hao Lo, Velia M Fowler","doi":"10.1182/bloodadvances.2025016100","DOIUrl":"https://doi.org/10.1182/bloodadvances.2025016100","url":null,"abstract":"<p><p>Mammalian red blood cells are generated via a terminal erythroid differentiation pathway culminating in cell polarization and enucleation. Actin filament (F-actin) polymerization is critical for enucleation, but the molecular regulatory mechanisms remain poorly understood. We utilized publicly available RNA-seq and proteomics datasets to mine for actin-regulatory factors differentially expressed during human erythroid differentiation and discovered that a focal adhesion protein-Tensin1-dramatically increases in expression late in differentiation. Remarkably, we found that differentiating human CD34+ cells express a novel truncated form of Tensin1 (eTNS1; Mr ~125 kDa) missing the N-terminal half of the protein containing the actin-binding domain, due to an internal mRNA translation start site resulting in a unique exon 1E. The region upstream of eTNS1 has features of an active erythroid promoter, demonstrating increasing chromatin accessibility during terminal differentiation, paralleling increasing gene expression. Sequence comparisons across species indicate that eTNS1 is expressed in humans and non-human primates, but not in zebrafish, mice or other rodents. Confocal microscopy showed that eTNS1 localized to the cytoplasm during terminal erythroid differentiation, but surprisingly, did not appear to form focal adhesions nor to colocalize with F-actin. Knocking out eTNS1 did not affect terminal differentiation or assembly of the spectrin membrane skeleton but led to reduced F-actin assembly and abnormal organization in polarized and enucleating erythroblasts, resulting in impaired enucleation efficiency. We conclude that eTNS1 is a novel regulator of F-actin during human erythroid terminal differentiation that is required for efficient enucleation.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145237917","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}