Pub Date : 2026-01-15DOI: 10.1182/blood.2025031427
Oreofe O Odejide,Gregory A Abel
{"title":"Patient-reported outcomes: a Polaris for POLARIX.","authors":"Oreofe O Odejide,Gregory A Abel","doi":"10.1182/blood.2025031427","DOIUrl":"https://doi.org/10.1182/blood.2025031427","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"37 1","pages":"219-220"},"PeriodicalIF":20.3,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145986446","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}
Pub Date : 2026-01-15DOI: 10.1182/blood.2025031255
Juan-Jose Garces,Francesco Maura
{"title":"Time to say adieu to FISH in myeloma diagnostics.","authors":"Juan-Jose Garces,Francesco Maura","doi":"10.1182/blood.2025031255","DOIUrl":"https://doi.org/10.1182/blood.2025031255","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"47 1","pages":"221-222"},"PeriodicalIF":20.3,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145986449","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}
ANKRD26-related thrombocytopenia (THC2) is a rare inherited platelet disorder caused by germline variants in the 5' untranslated region (UTR) of ANKRD26. While prior studies using in vitro models or isolated case reports have suggested impaired megakaryopoiesis as a central mechanism, detailed insights have remained elusive-primarily due to the rarity, fragility, and heterogeneity of megakaryocytes. Here, we present a comprehensive, cross-validated analysis of bone marrow samples from four independent THC2 patients, integrating single-cell transcriptomics and ex vivo functional profiling. Across all patients, we analyzed CD34⁺ hematopoietic stem and progenitor cells (HSPCs) (47,281 THC2-HSPCs vs. 51,907 control cells) and primary megakaryocytes (pMKs) (7,309 THC2-pMKs vs. 5,077 controls), uncovering a consistent pattern of megakaryocyte progenitors (MkP) expansion and a marked reduction in polyploid megakaryocytes-indicating a conserved pathophysiologic phenotype. In our index patient, we identified the 5'UTR single-nucleotide variant in ANKRD26 that led to significantly elevated expression across four megakaryocyte-lineage subsets-spanning multipotent progenitors, common myeloid progenitors, megakaryocyte-erythroid progenitors, and MkPs-as well as in terminally enriched pMKs. Spatial transcriptomics and confocal imaging localized ANKRD26 to the centrosome, implicating it in mitotic regulation during megakaryocyte maturation. Mechanistically, we discovered that elevated ANKRD26 induces apoptosis in polyploid megakaryocytes via JUNB-mediated transcriptional activation of CDKN1A (p21)-operating independently of the canonical p53-PIDDosome axis. This multi-patient study provides the most comprehensive cellular and molecular portrait of ANKRD26-driven thrombocytopenia to date, offering novel insights into defective megakaryopoiesis and identifying candidate therapeutic targets to restore platelet production.
ANKRD26相关血小板减少症（THC2）是一种罕见的遗传性血小板疾病，由ANKRD26的5'非翻译区（UTR）的种系变异引起。虽然先前使用体外模型或孤立病例报告的研究表明巨核细胞生成受损是中心机制，但由于巨核细胞的稀有性、脆弱性和异质性，详细的见解仍然难以捉摸。在这里，我们提出了一个全面的、交叉验证的分析，从四个独立的THC2患者的骨髓样本，整合单细胞转录组学和离体功能分析。在所有患者中，我们分析了CD34 +造血干细胞和祖细胞（HSPCs）（47,281个THC2-HSPCs vs. 51,907个对照细胞）和原代巨核细胞（pMKs）（7,309个THC2-pMKs vs. 5,077个对照细胞），发现了巨核细胞祖细胞（MkP）扩增的一致模式和多倍体巨核细胞的显着减少-表明了保守的病理生理表型。在我们的患者中，我们发现ANKRD26中的5'UTR单核苷酸变异导致四个巨核细胞谱系亚群的表达显著升高，这些亚群包括多能祖细胞、普通髓系祖细胞、巨核红细胞祖细胞和mpp，以及最终富集的pmk。空间转录组学和共聚焦成像将ANKRD26定位在中心体上，暗示其参与巨核细胞成熟过程中的有丝分裂调节。在机制上，我们发现升高的ANKRD26通过junb介导的CDKN1A （p21）的转录激活诱导多倍体巨核细胞凋亡-独立于典型的p53-PIDDosome轴。这项多患者研究提供了迄今为止ankrd26驱动的血小板减少症最全面的细胞和分子图谱，为巨核生成缺陷提供了新的见解，并确定了恢复血小板生成的候选治疗靶点。
{"title":"Single-Cell Profiling of ANKRD26 Thrombocytopenia Reveals Progenitor Expansion and Polyploid Apoptosis via JUNB-p21.","authors":"Lin Chen,Lanyue Hu,Xiaofan Liu,Xiaojie Wang,Chengning Tan,Maoshan Chen,Xiaoting Yin,Wuchen Yang,Zhenxing Yang,Yang Xiang,Yanni Xiao,Lixin Xiang,Xiaoliang Li,Jiuxuan Li,Weiwei Zhang,Xueying Wang,Chuanchuan Lin,Yangyang Zhang,Wanling Gou,Yangzhou Jiang,Teng Yu,Renchi Yang,Calvin Li,Qian Ran,Zhongjun Li","doi":"10.1182/blood.2025030017","DOIUrl":"https://doi.org/10.1182/blood.2025030017","url":null,"abstract":"ANKRD26-related thrombocytopenia (THC2) is a rare inherited platelet disorder caused by germline variants in the 5' untranslated region (UTR) of ANKRD26. While prior studies using in vitro models or isolated case reports have suggested impaired megakaryopoiesis as a central mechanism, detailed insights have remained elusive-primarily due to the rarity, fragility, and heterogeneity of megakaryocytes. Here, we present a comprehensive, cross-validated analysis of bone marrow samples from four independent THC2 patients, integrating single-cell transcriptomics and ex vivo functional profiling. Across all patients, we analyzed CD34⁺ hematopoietic stem and progenitor cells (HSPCs) (47,281 THC2-HSPCs vs. 51,907 control cells) and primary megakaryocytes (pMKs) (7,309 THC2-pMKs vs. 5,077 controls), uncovering a consistent pattern of megakaryocyte progenitors (MkP) expansion and a marked reduction in polyploid megakaryocytes-indicating a conserved pathophysiologic phenotype. In our index patient, we identified the 5'UTR single-nucleotide variant in ANKRD26 that led to significantly elevated expression across four megakaryocyte-lineage subsets-spanning multipotent progenitors, common myeloid progenitors, megakaryocyte-erythroid progenitors, and MkPs-as well as in terminally enriched pMKs. Spatial transcriptomics and confocal imaging localized ANKRD26 to the centrosome, implicating it in mitotic regulation during megakaryocyte maturation. Mechanistically, we discovered that elevated ANKRD26 induces apoptosis in polyploid megakaryocytes via JUNB-mediated transcriptional activation of CDKN1A (p21)-operating independently of the canonical p53-PIDDosome axis. This multi-patient study provides the most comprehensive cellular and molecular portrait of ANKRD26-driven thrombocytopenia to date, offering novel insights into defective megakaryopoiesis and identifying candidate therapeutic targets to restore platelet production.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"84 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145971792","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}
Pub Date : 2026-01-13DOI: 10.1182/blood.2025029535
Jamie E Flerlage,Angela M Feraco,Yiwang Zhou,Ying Zheng,Jia Liang,John T Lucas,Alison M Friedmann,Howard J Weinstein,Torunn I Yock,Barry L Shulkin,Sue C Kaste,Lianna J Marks,Matthew J Ehrhardt,Stephanie B Dixon,Scott Howard,Pedro de Alarcon,Sandra Luna-Fineman,Amy E Geddis,Eric C Larsen,Karen J Marcus,Amy Billett,Sarah S Donaldson,Melissa M Hudson,Monika L Metzger,Matthew J Krasin,Michael P Link
The Pediatric Hodgkin Consortium (PHC) hypothesized that increasing chemotherapeutic dose-density for Hodgkin lymphoma (HL) they could increase the complete response rate among favorable risk patients with HL after 8 weeks of Stanford V compared to 8 weeks of VAMP. This would translate to a decrease in patients who required radiation therapy (RT) to achieve a cure. HOD08 (NCT00846742) was a phase II multicenter investigator-initiated single- arm trial for patients ≤ 21 years of age with previously untreated stage IA or IIA HL without mediastinal bulk or extranodal disease extension and fewer than three sites of disease. Treatment consisted of a modified 8-week Stanford V regimen (vinblastine, doxorubicin, vincristine, bleomycin, mechlorethamine, etoposide and prednisone). Modified tailored field RT was administered only to disease sites achieving less than a CR. The primary objective was to increase CR rate after 8 weeks of chemotherapy by at least 20% (from an estimated 44% to 64%) compared to patients treated on a previous trial (HOD99). HOD08 enrolled 85 patients with HL and 72 were evaluable for the primary objective of whom 55 (76.4%) achieved a CR at all sites and did not receive RT. The 5-year event-free survival (EFS) and overall survival (OS) rates for the entire cohort were 87.4% (95% confidence interval (CI) 80.4%-95.0%) and 98.7% (95% CI 96.2%-100%), respectively. A dose-dense modified Stanford V regimen reduced the proportion of low-risk pediatric patients with HL who received RT while maintaining excellent outcomes. NCT00846742.
儿童霍奇金联盟（PHC）假设，增加霍奇金淋巴瘤（HL）的化疗剂量密度，与8周VAMP相比，在8周Stanford V治疗后，他们可以提高有利风险HL患者的完全缓解率。这将转化为需要放射治疗（RT）来治愈的患者的减少。HOD08 （NCT00846742）是一项II期多中心研究人员发起的单臂试验，适用于年龄≤21岁的未接受过治疗的IA期或IIA期HL患者，患者无纵隔肿大或结外疾病延伸，且疾病部位少于3个。治疗包括改良的8周Stanford V方案（长春花碱、阿霉素、长春新碱、博来霉素、氯胺酮、依托泊苷和强的松）。改良的定制野RT仅用于达到CR以下的疾病部位。主要目标是与先前试验（HOD99）治疗的患者相比，8周化疗后CR率至少增加20%（从估计的44%增加到64%）。HOD08纳入了85例HL患者，其中72例可评估为主要目标，其中55例（76.4%）在所有部位达到CR，未接受rt治疗。整个队列的5年无事件生存率（EFS）和总生存率（OS）分别为87.4%（95%置信区间（CI） 80.4%-95.0%）和98.7% （95% CI 96.2%-100%）。剂量密集改良的Stanford V方案降低了接受RT治疗的低风险儿科HL患者的比例，同时保持了良好的预后。NCT00846742。
{"title":"Dose-dense chemotherapy enables elimination of RT for majority of low-risk pediatric Hodgkin lymphoma: PHC study HOD08.","authors":"Jamie E Flerlage,Angela M Feraco,Yiwang Zhou,Ying Zheng,Jia Liang,John T Lucas,Alison M Friedmann,Howard J Weinstein,Torunn I Yock,Barry L Shulkin,Sue C Kaste,Lianna J Marks,Matthew J Ehrhardt,Stephanie B Dixon,Scott Howard,Pedro de Alarcon,Sandra Luna-Fineman,Amy E Geddis,Eric C Larsen,Karen J Marcus,Amy Billett,Sarah S Donaldson,Melissa M Hudson,Monika L Metzger,Matthew J Krasin,Michael P Link","doi":"10.1182/blood.2025029535","DOIUrl":"https://doi.org/10.1182/blood.2025029535","url":null,"abstract":"The Pediatric Hodgkin Consortium (PHC) hypothesized that increasing chemotherapeutic dose-density for Hodgkin lymphoma (HL) they could increase the complete response rate among favorable risk patients with HL after 8 weeks of Stanford V compared to 8 weeks of VAMP. This would translate to a decrease in patients who required radiation therapy (RT) to achieve a cure. HOD08 (NCT00846742) was a phase II multicenter investigator-initiated single- arm trial for patients ≤ 21 years of age with previously untreated stage IA or IIA HL without mediastinal bulk or extranodal disease extension and fewer than three sites of disease. Treatment consisted of a modified 8-week Stanford V regimen (vinblastine, doxorubicin, vincristine, bleomycin, mechlorethamine, etoposide and prednisone). Modified tailored field RT was administered only to disease sites achieving less than a CR. The primary objective was to increase CR rate after 8 weeks of chemotherapy by at least 20% (from an estimated 44% to 64%) compared to patients treated on a previous trial (HOD99). HOD08 enrolled 85 patients with HL and 72 were evaluable for the primary objective of whom 55 (76.4%) achieved a CR at all sites and did not receive RT. The 5-year event-free survival (EFS) and overall survival (OS) rates for the entire cohort were 87.4% (95% confidence interval (CI) 80.4%-95.0%) and 98.7% (95% CI 96.2%-100%), respectively. A dose-dense modified Stanford V regimen reduced the proportion of low-risk pediatric patients with HL who received RT while maintaining excellent outcomes. NCT00846742.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"35 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145961448","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}
Pub Date : 2026-01-12DOI: 10.1182/blood.2024028031
Kevin Lee,Cih-Li Hong,Wimeth Dissanayake,Gulzada Kulzhanova,Alexander Noel Pfeffer,Haiyin Li,Senthil Sivakumar,Zi Yin,Emily R Quarato,Lauren Benoodt,Jeevisha Bajaj,Chike Cao,Chia-Lung Wu,Laura M Calvi,Shu-Chi Allison Yeh
Clonal hematopoiesis of indeterminate potential (CHIP) is driven by hematopoietic stem cells (HSCs) carrying leukemia-associated mutations that expand in the bone marrow. Several prior studies have revealed that the spatial organization of hematopoietic cells in the bone marrow impacts clonal behaviors. Specifically, leukemic blasts have been found to expand almost exclusively in a subset of marrow cavities that are undergoing active bone remodeling, but whether these cavities also support the expansion of non-malignant mutant clones has never been visualized. Although it is widely appreciated that systemic inflammation promotes the selection of mutant clones, this view has emerged without considering the potential heterogeneity in the inflammatory landscape shaped by local bone remodeling. Leveraging intravital imaging and a murine model of CHIP (Tet2+/-), we demonstrated transcriptional and functional compartmentalization of the marrow microenvironment. Macrophages within non-resorptive cavities are inherently anti-inflammatory, which suppresses disease-initiating Tet2+/- cells while preserving the healthy counterpart. Time-lapse imaging further revealed non-transient association between Tet2+/- clones and CD206+ macrophages. Spatially resolved single-cell transcriptomic profiling and functional assessment revealed that physiological bone remodeling influences CD206+ macrophage plasticity and cytokine secretion which regulate the clonal burden. Additionally, anti-tumor immunity alteration within the microenvironment occurred as early as the formation of initial clones. Suppressing bone remodeling with zoledronate or targeting macrophage-associated niche factors mitigated clonal development. Collectively, our study reveals a previously unrecognized inflammatory landscape shaped by local bone remodeling. The finding presents targetable mechanisms and warrants further studies on the use and precautions of bone-modulating management in clonal blood disorders.
{"title":"Compartmentalized inflammatory landscape and macrophage plasticity regulate Tet2+/- mediated clonal hematopoiesis.","authors":"Kevin Lee,Cih-Li Hong,Wimeth Dissanayake,Gulzada Kulzhanova,Alexander Noel Pfeffer,Haiyin Li,Senthil Sivakumar,Zi Yin,Emily R Quarato,Lauren Benoodt,Jeevisha Bajaj,Chike Cao,Chia-Lung Wu,Laura M Calvi,Shu-Chi Allison Yeh","doi":"10.1182/blood.2024028031","DOIUrl":"https://doi.org/10.1182/blood.2024028031","url":null,"abstract":"Clonal hematopoiesis of indeterminate potential (CHIP) is driven by hematopoietic stem cells (HSCs) carrying leukemia-associated mutations that expand in the bone marrow. Several prior studies have revealed that the spatial organization of hematopoietic cells in the bone marrow impacts clonal behaviors. Specifically, leukemic blasts have been found to expand almost exclusively in a subset of marrow cavities that are undergoing active bone remodeling, but whether these cavities also support the expansion of non-malignant mutant clones has never been visualized. Although it is widely appreciated that systemic inflammation promotes the selection of mutant clones, this view has emerged without considering the potential heterogeneity in the inflammatory landscape shaped by local bone remodeling. Leveraging intravital imaging and a murine model of CHIP (Tet2+/-), we demonstrated transcriptional and functional compartmentalization of the marrow microenvironment. Macrophages within non-resorptive cavities are inherently anti-inflammatory, which suppresses disease-initiating Tet2+/- cells while preserving the healthy counterpart. Time-lapse imaging further revealed non-transient association between Tet2+/- clones and CD206+ macrophages. Spatially resolved single-cell transcriptomic profiling and functional assessment revealed that physiological bone remodeling influences CD206+ macrophage plasticity and cytokine secretion which regulate the clonal burden. Additionally, anti-tumor immunity alteration within the microenvironment occurred as early as the formation of initial clones. Suppressing bone remodeling with zoledronate or targeting macrophage-associated niche factors mitigated clonal development. Collectively, our study reveals a previously unrecognized inflammatory landscape shaped by local bone remodeling. The finding presents targetable mechanisms and warrants further studies on the use and precautions of bone-modulating management in clonal blood disorders.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"84 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145955489","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}
Pub Date : 2026-01-12DOI: 10.1182/blood.2025029196
Janet L Kwiatkowski,Alexis A Thompson,Jennifer Schneiderman,Isabelle Thuret,Andreas E Kulozik,Evangelia Yannaki,Marina Cavazzana,Suradej Hongeng,Timothy S Olson,Martin G Sauer,Adrian J Thrasher,Ashutosh Lal,John Ej Rasko,Joachim B Kunz,Melissa A Kinney,Anjulika Chawla,Shamshad Ali,Ge Tao,Himal Thakar,Clark Paramore,Niki Witthuhn,Mark C Walters,Franco Locatelli
Betibeglogene autotemcel (beti-cel) gene therapy for transfusion-dependent β-thalassemia (TDT) involves autologous transplantation of hematopoietic stem and progenitor cells transduced with a modified β-globin gene to produce functional adult hemoglobin (HbAT87Q). Sixty-three participants with TDT (median [range] age: 17 [4-35] years) received beti-cel in phase 1/2 (n = 22) or phase 3 (n = 41) studies and enrolled in the long-term follow-up LTF-303 study (clinicaltrials.gov/NCT02633943; median [range] follow-up: 5.9 [2.9-10.1] years). Manufacturing refinements in phase 3 increased transduction efficiency, resulting in higher drug product vector copy number and HbAT87Q levels, which translated into higher hemoglobin and transfusion independence (TI) rates compared with phase 1/2. TI was achieved by 68.2% (15/22) of phase 1/2 participants (median weighted average Hb during TI, 10.2 g/dL) and 90.2% (37/41) of phase 3 participants (median, 11.2 g/dL) and was sustained through last follow-up. Treatment efficacy was similar across ages and TDT genotypes. Among participants achieving TI, 73% (38/52) had discontinued iron chelation at last follow-up, with no increase in liver iron concentration. Markers of ineffective erythropoiesis, including serum transferrin receptor and erythropoietin, improved with restoration of iron homeostasis. Health-related quality-of-life assessment scores showed durable improvements. No malignancies, insertional oncogenesis, or vector-derived replication-competent lentivirus were reported. These findings establish beti-cel as a durable, one-time therapy that achieves TI, restores iron balance, and improves quality of life, offering a potentially curative treatment option for people with TDT.
{"title":"Long-term efficacy and safety results of betibeglogene autotemcel gene therapy for transfusion-dependent β-thalassemia.","authors":"Janet L Kwiatkowski,Alexis A Thompson,Jennifer Schneiderman,Isabelle Thuret,Andreas E Kulozik,Evangelia Yannaki,Marina Cavazzana,Suradej Hongeng,Timothy S Olson,Martin G Sauer,Adrian J Thrasher,Ashutosh Lal,John Ej Rasko,Joachim B Kunz,Melissa A Kinney,Anjulika Chawla,Shamshad Ali,Ge Tao,Himal Thakar,Clark Paramore,Niki Witthuhn,Mark C Walters,Franco Locatelli","doi":"10.1182/blood.2025029196","DOIUrl":"https://doi.org/10.1182/blood.2025029196","url":null,"abstract":"Betibeglogene autotemcel (beti-cel) gene therapy for transfusion-dependent β-thalassemia (TDT) involves autologous transplantation of hematopoietic stem and progenitor cells transduced with a modified β-globin gene to produce functional adult hemoglobin (HbAT87Q). Sixty-three participants with TDT (median [range] age: 17 [4-35] years) received beti-cel in phase 1/2 (n = 22) or phase 3 (n = 41) studies and enrolled in the long-term follow-up LTF-303 study (clinicaltrials.gov/NCT02633943; median [range] follow-up: 5.9 [2.9-10.1] years). Manufacturing refinements in phase 3 increased transduction efficiency, resulting in higher drug product vector copy number and HbAT87Q levels, which translated into higher hemoglobin and transfusion independence (TI) rates compared with phase 1/2. TI was achieved by 68.2% (15/22) of phase 1/2 participants (median weighted average Hb during TI, 10.2 g/dL) and 90.2% (37/41) of phase 3 participants (median, 11.2 g/dL) and was sustained through last follow-up. Treatment efficacy was similar across ages and TDT genotypes. Among participants achieving TI, 73% (38/52) had discontinued iron chelation at last follow-up, with no increase in liver iron concentration. Markers of ineffective erythropoiesis, including serum transferrin receptor and erythropoietin, improved with restoration of iron homeostasis. Health-related quality-of-life assessment scores showed durable improvements. No malignancies, insertional oncogenesis, or vector-derived replication-competent lentivirus were reported. These findings establish beti-cel as a durable, one-time therapy that achieves TI, restores iron balance, and improves quality of life, offering a potentially curative treatment option for people with TDT.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"7 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145955943","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}
Pub Date : 2026-01-12DOI: 10.1182/blood.2025030137
Elizabeth A Traxler,Quynn Hotan,Yue Shao,Chad Komar,Qingzhou Chen,Megan S Saari,A Josephine Thrasher,Shuchen Yang,Kunhua Qin,Michelle Wang,Scott A Peslak,Osheiza Abdulmalik,Belinda M Giardine,Cheryl A Keller,Ross C Hardison,Andy J Minn,Eugene Khandros,Junwei Shi,Gerd A Blobel
Reactivating the fetal globin genes HBG1 and HBG2 in adult erythroid cells represents a validated therapeutic approach for hemoglobinopathies. Central mediators of the fetal-to-adult hemoglobin transition include the direct transcriptional HBG1/2 repressors BCL11A1,2, LRF3, and NFIA/X4. Limited-scale screens have attempted to expand the regulatory circuity surrounding fetal globin silencing, but systematic genome-wide dissection of such pathways is lacking. We employed a two-tiered genetic screening strategy - a novel CRISPR-Cas12a-based screening platform followed by a domain-focused CRISPR-Cas9 screen - to interrogate all known human coding genes for their impact on HBG1/2 regulation and erythroid cellular fitness, generating a comprehensive resource for the field. Among the top hits was PTPA, an activator of the serine-threonine phosphatase PP2A whose loss elevates HBG1/2 levels while preserving erythroid differentiation. Phenotypic rescue experiments revealed that PTPA silences HBG1/2 expression primarily by regulating BCL11A expression. To our knowledge, this study represents the most comprehensive CRISPR dissection of HBG regulation to date, highlighting the power of Cas12a-based genome-scale screening for uncovering disease-relevant pathways.
{"title":"Optimized CRISPR-Cas12a genome-wide screen reveals PTPA phosphatase pathway in fetal hemoglobin silencing.","authors":"Elizabeth A Traxler,Quynn Hotan,Yue Shao,Chad Komar,Qingzhou Chen,Megan S Saari,A Josephine Thrasher,Shuchen Yang,Kunhua Qin,Michelle Wang,Scott A Peslak,Osheiza Abdulmalik,Belinda M Giardine,Cheryl A Keller,Ross C Hardison,Andy J Minn,Eugene Khandros,Junwei Shi,Gerd A Blobel","doi":"10.1182/blood.2025030137","DOIUrl":"https://doi.org/10.1182/blood.2025030137","url":null,"abstract":"Reactivating the fetal globin genes HBG1 and HBG2 in adult erythroid cells represents a validated therapeutic approach for hemoglobinopathies. Central mediators of the fetal-to-adult hemoglobin transition include the direct transcriptional HBG1/2 repressors BCL11A1,2, LRF3, and NFIA/X4. Limited-scale screens have attempted to expand the regulatory circuity surrounding fetal globin silencing, but systematic genome-wide dissection of such pathways is lacking. We employed a two-tiered genetic screening strategy - a novel CRISPR-Cas12a-based screening platform followed by a domain-focused CRISPR-Cas9 screen - to interrogate all known human coding genes for their impact on HBG1/2 regulation and erythroid cellular fitness, generating a comprehensive resource for the field. Among the top hits was PTPA, an activator of the serine-threonine phosphatase PP2A whose loss elevates HBG1/2 levels while preserving erythroid differentiation. Phenotypic rescue experiments revealed that PTPA silences HBG1/2 expression primarily by regulating BCL11A expression. To our knowledge, this study represents the most comprehensive CRISPR dissection of HBG regulation to date, highlighting the power of Cas12a-based genome-scale screening for uncovering disease-relevant pathways.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"15 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145956180","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}
Pub Date : 2026-01-09DOI: 10.1182/blood.2025031080
Jana Gawron, Marie Czech, Tamina Rückert, Verena Holzmüller, Grigor Andreev, Ann-Cathrin Burk, Alina Hartmann, Sangya Chatterjee, Geoffroy Andrieux, Franziska Elisabeth Marquard, Anna-Sophia Baur, Anna-Verena Stell, Máté Krausz, Lukas M Braun, Natascha Osswald, Wolfgang Melchinger, Tobias Wertheimer, Andrea Isabel Proano-Vasco, Kristina Maas-Bauer, Annette Schmitt-Graeff, Melanie Boerries, Natalie Köhler, Francis Ayuketang Ayuk, Christoph Schell, Michael Quante, Robert Zeiser
Acute graft-versus-host disease (aGVHD) is a major cause of death after allogeneic hematopoietic cell transplantation (allo-HCT) and patients with steroid-refractory aGVHD have a dismal prognosis. We have previously shown that the enteroendocrine hormone glucagon-like peptide-2 (GLP-2) has tissue regenerative activity in the lower GI in mice and patients with steroid-refractory aGVHD. Here we explored the tissue protective effect of the enteroendocrine hormone gastrin for aGVHD of the stomach. We observed that aGVHD caused a loss of gastrin-producing G-cells and parietal cells (PCs) and an increase of pH in the stomach, while allogeneic T cells infiltrated the stomach wall. Pentagastrin treatment of aGVHD mice rescued the loss of PCs, normalized the pH in the stomach, increased stomach stem cell marker expression and abundance of LGR5+ cells, and changes in the stomach microbiome. Gastrin also increased the viability of stomach and small intestine organoids in vitro. Gast-/- mice experienced more severe aGVHD in the intestine and liver compared to WT mice, which was rescued by pentagastrin-treatment. In patients developing aGVHD, low gastrin levels in stomach biopsies were connected to reduced survival. Moreover, gastrin expression in the stomach correlated with aGVHD severity and tissue damage scores in independent patient cohorts. This study delineates the protective role of gastrin in aGVHD of the stomach in mice and patients and provides a rationale for therapeutic use of pentagastrin in a clinical trial for patients with aGVHD.
{"title":"Gastrin for the treatment of acute graft-versus-host disease of the stomach.","authors":"Jana Gawron, Marie Czech, Tamina Rückert, Verena Holzmüller, Grigor Andreev, Ann-Cathrin Burk, Alina Hartmann, Sangya Chatterjee, Geoffroy Andrieux, Franziska Elisabeth Marquard, Anna-Sophia Baur, Anna-Verena Stell, Máté Krausz, Lukas M Braun, Natascha Osswald, Wolfgang Melchinger, Tobias Wertheimer, Andrea Isabel Proano-Vasco, Kristina Maas-Bauer, Annette Schmitt-Graeff, Melanie Boerries, Natalie Köhler, Francis Ayuketang Ayuk, Christoph Schell, Michael Quante, Robert Zeiser","doi":"10.1182/blood.2025031080","DOIUrl":"https://doi.org/10.1182/blood.2025031080","url":null,"abstract":"<p><p>Acute graft-versus-host disease (aGVHD) is a major cause of death after allogeneic hematopoietic cell transplantation (allo-HCT) and patients with steroid-refractory aGVHD have a dismal prognosis. We have previously shown that the enteroendocrine hormone glucagon-like peptide-2 (GLP-2) has tissue regenerative activity in the lower GI in mice and patients with steroid-refractory aGVHD. Here we explored the tissue protective effect of the enteroendocrine hormone gastrin for aGVHD of the stomach. We observed that aGVHD caused a loss of gastrin-producing G-cells and parietal cells (PCs) and an increase of pH in the stomach, while allogeneic T cells infiltrated the stomach wall. Pentagastrin treatment of aGVHD mice rescued the loss of PCs, normalized the pH in the stomach, increased stomach stem cell marker expression and abundance of LGR5+ cells, and changes in the stomach microbiome. Gastrin also increased the viability of stomach and small intestine organoids in vitro. Gast-/- mice experienced more severe aGVHD in the intestine and liver compared to WT mice, which was rescued by pentagastrin-treatment. In patients developing aGVHD, low gastrin levels in stomach biopsies were connected to reduced survival. Moreover, gastrin expression in the stomach correlated with aGVHD severity and tissue damage scores in independent patient cohorts. This study delineates the protective role of gastrin in aGVHD of the stomach in mice and patients and provides a rationale for therapeutic use of pentagastrin in a clinical trial for patients with aGVHD.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":23.1,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145942511","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}
Pub Date : 2026-01-09DOI: 10.1182/blood.2025028645
Stefan N Constantinescu,William Vainchenker,Christian Pecquet
JAK inhibitors have changed the treatment landscape of myeloproliferative neoplasms, graft-versus host and several autoimmune conditions. While approved JAK inhibitors generally target the JAK2 kinase domain, and several also the JAK1 kinase domain in active form (type I inhibition), new inhibitors have progressed to clinical trials that either exhibit a type II mechanism of inhibition of the kinase domain in an inactive state or that target the pseudokinase domain with potential preference or specificity for the JAK2 V617F mutant. This is the most prevalent mutant in myeloproliferative neoplasms. An ideal inhibitor would target persistently activated JAK2 in MPNs, eradicate the clone or induce deep molecular remission in addition to clinical and hematological remission and spare wild type JAK2 that is critical for hematopoiesis and immune response. We discuss perspectives of these and other modes of JAK inhibition and primary as well as secondary/exploratory study endpoints in clinical trials design, along with potential biomarker correlates to evaluate potential efficacy of the next generation versus conventional JAK inhibitors.
{"title":"Next-Generation JAK Inhibitors in the Treatment of Myeloproliferative Neoplasms.","authors":"Stefan N Constantinescu,William Vainchenker,Christian Pecquet","doi":"10.1182/blood.2025028645","DOIUrl":"https://doi.org/10.1182/blood.2025028645","url":null,"abstract":"JAK inhibitors have changed the treatment landscape of myeloproliferative neoplasms, graft-versus host and several autoimmune conditions. While approved JAK inhibitors generally target the JAK2 kinase domain, and several also the JAK1 kinase domain in active form (type I inhibition), new inhibitors have progressed to clinical trials that either exhibit a type II mechanism of inhibition of the kinase domain in an inactive state or that target the pseudokinase domain with potential preference or specificity for the JAK2 V617F mutant. This is the most prevalent mutant in myeloproliferative neoplasms. An ideal inhibitor would target persistently activated JAK2 in MPNs, eradicate the clone or induce deep molecular remission in addition to clinical and hematological remission and spare wild type JAK2 that is critical for hematopoiesis and immune response. We discuss perspectives of these and other modes of JAK inhibition and primary as well as secondary/exploratory study endpoints in clinical trials design, along with potential biomarker correlates to evaluate potential efficacy of the next generation versus conventional JAK inhibitors.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"29 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145937815","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}
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