Haematologica最新文献_第2页

Ex vivo correction of severe coagulation Factor VII deficiency in patient-derived 3D liver organoids. 患者来源的三维肝类器官严重凝血因子VII缺乏的体外矫正。

IF 10.1 1区医学

Haematologica Pub Date : 2025-10-09 DOI: 10.3324/haematol.2025.288046

Giacomo Roman,Knut H Lauritzen,Sean P Harrison,Anindita Bhattacharya,Marianne Seierstad Andresen,Marie-Christine Mowinckel,Barbora Smolkova,Carola E Henriksson,Heidi Glosli,Nina Iversen,Bernd Thiede,Gareth J Sullivan,Runar Almaas,Per Morten Sandset,Benedicte Stavik,Maria E Chollet

{"title":"Ex vivo correction of severe coagulation Factor VII deficiency in patient-derived 3D liver organoids.","authors":"Giacomo Roman,Knut H Lauritzen,Sean P Harrison,Anindita Bhattacharya,Marianne Seierstad Andresen,Marie-Christine Mowinckel,Barbora Smolkova,Carola E Henriksson,Heidi Glosli,Nina Iversen,Bernd Thiede,Gareth J Sullivan,Runar Almaas,Per Morten Sandset,Benedicte Stavik,Maria E Chollet","doi":"10.3324/haematol.2025.288046","DOIUrl":"https://doi.org/10.3324/haematol.2025.288046","url":null,"abstract":"Coagulation factor (F) VII deficiency is the most frequent among the rare, inherited bleeding disorders and is predominantly caused by missense mutations in the F7 gene. The disease phenotype ranges from asymptomatic cases to extremely severe hemorrhagic forms, requiring prophylactic injections with plasma-derived or recombinant FVII concentrates. In response, we have developed an autologous cell-based approach that corrects the disease-causing mutation in patient-derived induced pluripotent stem cells (iPSCs) and generates therapeutic, three-dimensional hepatic organoids (HOs). We report the CRISPRmediated correction of homozygous c.718G>C (p.G240R), a missense mutation associated with a severe, life-threatening bleeding phenotype. The HOs contain all liver cell types and exhibit key liver functions, including coagulation factor production. After correction, our data indicate that the patient-derived HOs secrete consistent amounts of functional FVII protein, resulting in improved thrombin generation times. These results represent a significant milestone toward the establishment of an autologous cell-based therapy for patients with FVII- and other coagulation factor deficiencies.","PeriodicalId":12964,"journal":{"name":"Haematologica","volume":"101 1","pages":""},"PeriodicalIF":10.1,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145246414","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}

引用次数: 0

Lineage bias in hematopoietic stem cells: more niche or intrinsic factors? 造血干细胞谱系偏倚：更多的生态位因素还是内在因素？

IF 10.1 1区医学

Haematologica Pub Date : 2025-10-09 DOI: 10.3324/haematol.2025.288704

Taha Bartu Hayal,Chuanfeng Wu

引用次数: 0

HES1 regulates bone marrow mesenchymal stromal cell function by suppressing NFATc2-mediated inflammation. HES1通过抑制nfatc2介导的炎症调节骨髓间充质间质细胞功能。

IF 10.1 1区医学

Haematologica Pub Date : 2025-10-02 DOI: 10.3324/haematol.2025.288138

Anthony Z Zhu,Zhilin Ma,Emily V Wolff,Sanghoon Lee,Zichen Lin,Zhenxia J Gao,Wei Du

{"title":"HES1 regulates bone marrow mesenchymal stromal cell function by suppressing NFATc2-mediated inflammation.","authors":"Anthony Z Zhu,Zhilin Ma,Emily V Wolff,Sanghoon Lee,Zichen Lin,Zhenxia J Gao,Wei Du","doi":"10.3324/haematol.2025.288138","DOIUrl":"https://doi.org/10.3324/haematol.2025.288138","url":null,"abstract":"The Notch target gene, Hairy and enhancer of split-1 (HES1), encodes a basic helixloop- helix transcriptional repressor that influences cell proliferation and differentiation in embryogenesis. Our previous studies indicate that HES1 is required for hematopoiesis under stress conditions. However, the role of HES1 in bone marrow (BM) microenvironment remains elucidated. By employing a BM niche specific Hes1 knockout mouse model, here we have investigated the role of HES1 in regulating mesenchymal stromal cell (MSC) homeostasis and their hematopoiesis supportive function. We found that while HES1 is dispensable in MSC in supporting steady-state hematopoiesis, Hes1fl/flPrx1Cre mice are hypersensitive to lipopolysaccharide (LPS) challenge. Deletion of Hes1 in the BM reduces MSC frequency and affects MSC self-renewal and proliferation. Hes1-deficient MSCs are less functional in supporting hematopoiesis both in vitro and ex vivo. Transcriptome analysis reveals that disruption of Hes1 in the BM stroma alters the expression of genes critical for cellular metabolism and inflammation. Pharmacological blockage of inflammation rescues Hes1-KO MSC phenotype and improves their hematopoiesis supportive function. Mechanistically, we show that HES1 binds to the conserved E boxes in the promoter of NFATc2, a member of the AT-rich interaction domain superfamily of DNA binding protein, to suppress NFATc2-mediated inflammation. Taken together, our study unveils a pivotal role of HES1 in maintaining BM MSC hemostasis and regulating their hematopoiesis supportive function.","PeriodicalId":12964,"journal":{"name":"Haematologica","volume":"114 1","pages":""},"PeriodicalIF":10.1,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145203966","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}

引用次数: 0

NFATc1 and NFATc2 regulate glucocorticoid resistance in pediatric T-cell acute lymphoblastic leukemia through modulation of cholesterol biosynthesis and the WNT/β-catenin pathway. NFATc1和NFATc2通过调节胆固醇生物合成和WNT/β-catenin通路调节儿童t细胞急性淋巴细胞白血病的糖皮质激素抵抗。

IF 10.1 1区医学

Haematologica Pub Date : 2025-10-02 DOI: 10.3324/haematol.2025.287651

Giulia Veltri,Alberto Peloso,Alice Cani,Elena Mariotto,Diana Corallo,Sanja Aveic,Loris Russo,Matilde Cescon,Giulia Santinon,Chiara Frasson,Katharina Simon,Alberto Arrighi,Egidio Iorio,Sonia Anna Minuzzo,Stefano Indraccolo,Sandra Marmiroli,Panagiotis Ntziachristos,Alessandra Biffi,Martina Pigazzi,Barbara Buldini,Silvia Bresolin,Valentina Serafin

{"title":"NFATc1 and NFATc2 regulate glucocorticoid resistance in pediatric T-cell acute lymphoblastic leukemia through modulation of cholesterol biosynthesis and the WNT/β-catenin pathway.","authors":"Giulia Veltri,Alberto Peloso,Alice Cani,Elena Mariotto,Diana Corallo,Sanja Aveic,Loris Russo,Matilde Cescon,Giulia Santinon,Chiara Frasson,Katharina Simon,Alberto Arrighi,Egidio Iorio,Sonia Anna Minuzzo,Stefano Indraccolo,Sandra Marmiroli,Panagiotis Ntziachristos,Alessandra Biffi,Martina Pigazzi,Barbara Buldini,Silvia Bresolin,Valentina Serafin","doi":"10.3324/haematol.2025.287651","DOIUrl":"https://doi.org/10.3324/haematol.2025.287651","url":null,"abstract":"The glucocorticoid (GC) resistance onset in pediatric T-cell Acute Lymphoblastic Leukemia (T-ALL) patients remains one of the biggest challenges in current cancer treatment. The mechanisms driving this resistance are still not fully understood, making it difficult to predict patient outcomes and to develop effective therapies. Our study uncovered critical insights into the biological processes underlying GC resistance, offering potential breakthroughs for future treatments. Building on our previous research on LCK kinase hyperactivation in GC-resistant T-ALL patients, we have now delved deeper into the LCK downstream NFAT transcription factor family's contribution to GC resistance. We discovered that, even at the time of diagnosis, GC resistant T-ALL patients exhibit an intrinsic low glucocorticoid receptor (GR) activity coupled with high NFATc1 and NFATc2 ones. This dysregulation creates a roadblock to effective GC therapy. Indeed, in the absence of either NFATc1 or NFATc2, the normal transcriptional activity of GR is restored, re-sensitizing the leukemia cells to dexamethasone treatment both in vitro and in vivo. This suggests that NFATc1 and NFATc2 are central to driving GC resistance, as they directly regulate crucial pathways like cholesterol biosynthesis and WNT/β-catenin signaling. The identification of NFAT transcription factors as key players in leukemia therapy resistance offers a promising target for future therapeutic strategies, potentially transforming the way we approach treatment for these challenging conditions or autoimmune disorders where glucocorticoids are a cornerstone of treatment.","PeriodicalId":12964,"journal":{"name":"Haematologica","volume":"53 1","pages":""},"PeriodicalIF":10.1,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145203970","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}

引用次数: 0

Long-term outcomes in FLT3-mutated acute myeloid leukemia after frontline hypomethylating agent, venetoclax and a FLT3 inhibitor. FLT3突变的急性髓系白血病在一线低甲基化药物、venetoclax和FLT3抑制剂治疗后的长期结局。

IF 10.1 1区医学

Haematologica Pub Date : 2025-10-02 DOI: 10.3324/haematol.2025.288553

Nicholas J Short,Sanam Loghavi,Musa Yilmaz,Omer Karrar,Kunhwa Kim,Courtney D Dinardo,Tapan M Kadia,Manuel Maroun,Gautam Borthakur,Ghayas C Issa,Joseph Jabbour,Betul Oran,Elizabeth J Shpall,Uday Popat,Keyur P Patel,Mark Routbort,Marina Konopleva,Farhad Ravandi,Hagop Kantarjian,Naval Daver

{"title":"Long-term outcomes in FLT3-mutated acute myeloid leukemia after frontline hypomethylating agent, venetoclax and a FLT3 inhibitor.","authors":"Nicholas J Short,Sanam Loghavi,Musa Yilmaz,Omer Karrar,Kunhwa Kim,Courtney D Dinardo,Tapan M Kadia,Manuel Maroun,Gautam Borthakur,Ghayas C Issa,Joseph Jabbour,Betul Oran,Elizabeth J Shpall,Uday Popat,Keyur P Patel,Mark Routbort,Marina Konopleva,Farhad Ravandi,Hagop Kantarjian,Naval Daver","doi":"10.3324/haematol.2025.288553","DOIUrl":"https://doi.org/10.3324/haematol.2025.288553","url":null,"abstract":"Triplet regimens with a hypomethylating agent, venetoclax and a FLT3 inhibitor yield high rates of response in newly diagnosed FLT3-mutated AML. However, the long-term outcomes and patterns of relapse with these triplet regimens are not well-established. In this retrospective analysis, 73 patients with newly diagnosed FLT3-mutated AML received a frontline FLT3 inhibitor-containing triplet regimen. The composite complete remission (CR) and CR with incomplete hematologic recovery (CRi) rate was 93%. Next-generation sequencing FLT3-ITD MRD negativity (sensitivity: 0.005%) was achieved in 60% of patients after cycle 2 and 90% after cycle 4. The estimated 3-year relapse-free survival (RFS) for FLT3-ITD-mutated and FLT3 TKD-mutated AML was 38% and 76%, respectively, and the 3-year overall survival (OS) was 45% and 76%, respectively. Neither age, NPM1 co-mutation, ELN 2022 risk, nor allogeneic stem cell transplantation in first remission significantly impacted OS. Baseline RAS pathway mutations were associated with poor long-term survival (3-year OS 22% versus 63% without RAS pathway mutation). FLT3 wild type relapses accounted for 65% of relapses, and new RAS pathway mutations were observed in 24% of relapses. Outcomes were poor after relapse (median OS of 6.1 months), particularly for those with persistently detectable FLT3 mutations. Triplet combinations of an HMA, venetoclax and a FLT3 inhibitor result in durable remission and encouraging long-term OS in older adults with newly diagnosed FLT3-mutated AML. However, better strategies to prevent FLT3 wild type relapses and to overcome RAS pathway-mediated resistance are still needed.","PeriodicalId":12964,"journal":{"name":"Haematologica","volume":"100 1","pages":""},"PeriodicalIF":10.1,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145203971","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}

引用次数: 0

Interim analysis of a multicenter study on patient-guided dose reduction of tyrosine kinase inhibitors in chronic myeloid leukemia: the RODEO study. 慢性髓性白血病患者指导下酪氨酸激酶抑制剂剂量降低的多中心研究中期分析：RODEO研究。

IF 10.1 1区医学

Haematologica Pub Date : 2025-10-02 DOI: 10.3324/haematol.2025.288516

Dina Nienke Lokhorst,Yolba Smit,Bart J F Van den Bemt,Rosella P M G Hermens,Marten R Nijziel,Asiong K-S Jie,Laura G M Daenen,Saskia K Klein,Eduardus F M Posthuma,Peter E Westerweel,Marjolein Donker,Mels Hoogendoorn,Charlotte L Bekker,Nicole M A Blijlevens

{"title":"Interim analysis of a multicenter study on patient-guided dose reduction of tyrosine kinase inhibitors in chronic myeloid leukemia: the RODEO study.","authors":"Dina Nienke Lokhorst,Yolba Smit,Bart J F Van den Bemt,Rosella P M G Hermens,Marten R Nijziel,Asiong K-S Jie,Laura G M Daenen,Saskia K Klein,Eduardus F M Posthuma,Peter E Westerweel,Marjolein Donker,Mels Hoogendoorn,Charlotte L Bekker,Nicole M A Blijlevens","doi":"10.3324/haematol.2025.288516","DOIUrl":"https://doi.org/10.3324/haematol.2025.288516","url":null,"abstract":"Patient-guided dose reduction, as explored in the RODEO study, offers a promising approach to alleviate the burden of tyrosine kinase inhibitor (TKI) therapy in chronic myeloid leukemia (CML). Supported by shared decision-making (SDM) and a patient decision aid, this strategy aims to reduce TKI toxicity while maintaining effectiveness. This interim analysis evaluates its effectiveness at six months, focusing on intervention failure, i.e., TKI dose re-escalation due to loss of major molecular remission (MMR) of BCR::ABL1 (>0.1%IS) or expected loss of MMR, and patient-reported healthrelated quality of life (HRQoL) and symptom burden. The SDM-process and decisional conflict are also evaluated. This is a prospective, single-arm, multicenter trial including 148 patients with chronicphase CML in at least MMR. Patients and their treating hematologists were engaged in an SDMprocess and selected a reduced TKI dose. BCR::ABL1 monitoring was conducted regularly; HRQoL and symptom burden was assessed using EORTC QLQ-C30, QLQ-CML24, and IL156. SDM and decisional conflict were evaluated via SDM-Q-9, SDM-Q-Doc, and the Decisional Conflict Scale. Of 146 patients analyzed, 2.8% experienced intervention failure at six months. Modest statistically significant improvements were seen in multiple symptom scales. SDM was well-evaluated, with low decisional conflict by patients. Patient-guided dose reduction appears safe and beneficial at six months followup.","PeriodicalId":12964,"journal":{"name":"Haematologica","volume":"10 1","pages":""},"PeriodicalIF":10.1,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145203952","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}

引用次数: 0

Real-world safety and efficacy of rADAMTS13 prophylaxis in congenital thrombotic thrombocytopenic purpura: experience from Polish patients previously treated with fresh frozen plasma. rADAMTS13预防先天性血栓性血小板减少性紫癜的实际安全性和有效性：来自波兰患者的新鲜冷冻血浆治疗经验

IF 10.1 1区医学

Haematologica Pub Date : 2025-10-02 DOI: 10.3324/haematol.2025.288561

Jerzy Windyga,Joanna Zdziarska,Magdalena Górska-Kosicka,Adela Gwozdowska,Miłosz Jazdon,Paweł Łaguna,Maria Szczepańska,Magdalena Wojdalska,Danuta Pietrys,Michał Taszner,Michał Witkowski,Beata Baran,Wojciech Młynarski

引用次数: 0

Diagnosis and management of adult telomere biology disorders. 成人端粒生物学疾病的诊断和治疗。

IF 10.1 1区医学

Haematologica Pub Date : 2025-10-02 DOI: 10.3324/haematol.2025.287739

Madeline Franke,Alejandro Ferrer,Mrinal M Patnaik

引用次数: 0

The added value of Bayesian interim analysis in randomized phase II and phase III clinical trials in hemato-oncology. 贝叶斯中期分析在血液肿瘤随机II期和III期临床试验中的附加价值。

IF 10.1 1区医学

Haematologica Pub Date : 2025-10-02 DOI: 10.3324/haematol.2025.288675

Anna J T Smit,Niek G Van der Maas,Bronno Van der Holt,Yvette Van Norden,Erik Van Werkhoven,Annette Juul Vangsted,Paula F Ypma,Heleen A Visser-Wisselaar,Rossella Troia,Mario Boccadoro,Bob Löwenberg,Jeroen J W M Janssen,Gert J Ossenkoppele,Fredrik Schjesvold,Pieter Sonneveld,Sonja Zweegman,Jurjen Versluis,Jan J Cornelissen

引用次数: 0

Intravenous immunoglobulins in the management of acute chest syndrome in two Jehovah's witnesses with sickle cell disease.

IF 10.1 1区医学

Haematologica Pub Date : 2025-10-02 DOI: 10.3324/haematol.2025.287956

Francesca Begali,Jacopo Ceolan,Silvia Vitale,Simone Villaboni,Matteo Merlo,Rachele Zamperini,Roberto Bertazzo,Soraia Ribeiro Luz,Filippo Mazzi,Lucia De Franceschi

引用次数: 0