Hematopoietic stem cells (HSCs) are heterogeneous, and the quality of HSCs - that is, 'transplantability' - is a key determinant for posttransplant hematopoietic reconstitution. However, molecular modalities of high-potency HSCs with superior transplantability still remain poorly understood. Here, we conducted large-scale single-clone serial-transplant experiments and tracked descendant cells of 288 HSC clones to quantify their intrinsic capability for hematopoietic reconstitution. Using integrated single-cell transcriptional, immunophenotypical, and Bayesian dynamic analyses, we uncovered three classes of HSC clones - 'Super', 'Flash', and 'Trickle' - that had higher output in the 1st generation but exhibited markedly different behavior in later generations. The 'Super'-class HSC clones comprised 4% of the HSCs and manifested persistent superior transplantability and balanced myeloid/lymphoid lineage outputs across generations in serial transplants. The 'Super'-class HSCs had a unique molecular signature, including low expression of CD27, that was distinct from previously known 'Classical HSC' signatures. Validation experiments indicated that CD27- HSCs had superior transplantability compared to CD27+ HSCs. Our study asserted an operational definition for 'Super' transplantability of HSCs, defined its molecular program, and suggested new directions for enriching high-potency HSCs in grafts.
{"title":"Heterogeneity of high-potency multilineage hematopoietic stem cells and identification of 'Super' transplantability.","authors":"Fang Dong,Sen Zhang,Caiying Zhu,Zining Yang,Lisha Wang,Yao Ma,Jiayi Lu,Xialin Li,Xiaofang Wang,Nini Wang,Shanshan Zhang,Miner Xie,Jinhong Wang,Xiaobing Zhang,Yawei Zheng,Shihui Ma,Hideo Ema,Hui Cheng,Sha Hao,Toshio Suda,Yu Lan,Bing Liu,Ping Zhu,Junren Chen,Tao Cheng","doi":"10.1182/blood.2024027872","DOIUrl":"https://doi.org/10.1182/blood.2024027872","url":null,"abstract":"Hematopoietic stem cells (HSCs) are heterogeneous, and the quality of HSCs - that is, 'transplantability' - is a key determinant for posttransplant hematopoietic reconstitution. However, molecular modalities of high-potency HSCs with superior transplantability still remain poorly understood. Here, we conducted large-scale single-clone serial-transplant experiments and tracked descendant cells of 288 HSC clones to quantify their intrinsic capability for hematopoietic reconstitution. Using integrated single-cell transcriptional, immunophenotypical, and Bayesian dynamic analyses, we uncovered three classes of HSC clones - 'Super', 'Flash', and 'Trickle' - that had higher output in the 1st generation but exhibited markedly different behavior in later generations. The 'Super'-class HSC clones comprised 4% of the HSCs and manifested persistent superior transplantability and balanced myeloid/lymphoid lineage outputs across generations in serial transplants. The 'Super'-class HSCs had a unique molecular signature, including low expression of CD27, that was distinct from previously known 'Classical HSC' signatures. Validation experiments indicated that CD27- HSCs had superior transplantability compared to CD27+ HSCs. Our study asserted an operational definition for 'Super' transplantability of HSCs, defined its molecular program, and suggested new directions for enriching high-potency HSCs in grafts.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"12 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143862030","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 : 2025-04-21DOI: 10.1182/blood.2025028833
Kai Rejeski,Jaime Sanz,Teng Fei,Monica S Nair,Hamza Hashmi,Abraham Avigdor,Ofrat Beyar-Katz,Veit L Bücklein,Kevin J Curran,Sigrun Einarsdottir,Jonathan H Esensten,Netta Glaubach,Noa Golan-Accav,Marina Gomez-Llobell,Iris Halamis,Orit Itzhaki,Frederick L Locke,Sham Mailankody,Ronit Marcus,Marcela V Maus,M Lia Palomba,Jae H Park,Marcelo C Pasquini,Sandeep S Raj,Sridevi Rajeeve,Gilles A Salles,Michael Scordo,Gunjan L Shah,Avichai Shimoni,Marion Subklewe,Tobias Tix,Saad Z Usmani,Ori Ben Valid,Yannis K Valtis,Tsila Zuckerman,Nirali N Shah,Miguel-Angel Perales,Roni Shouval
Immune effector cell-associated hematotoxicity (ICAHT) was recently introduced as a distinct toxicity category of CAR-T therapy. While a grading system based solely on neutrophil counts was proposed (hereafter termed N-ICAHT), the prevalence and prognostic impact of thrombocytopenia remains poorly defined. In this multicenter observational study, we systematically examined patterns of thrombocytopenia in 744 patients treated with commercial CD19 CAR-T for B-cell Non-Hodgkin Lymphoma (B-NHL). We developed a grading system termed T-ICAHT with thresholds that closely aligned with N-ICAHT - based on depth, duration and timing of thrombocytopenia. In the core NHL dataset, 43% of patients developed any-grade early T-ICAHT (day 0-30), with 23% developing severe (G3+) manifestations. Late T-ICAHT (day 31-100) was observed in 42% (G3+: 13%). While T-ICAHT and N-ICAHT gradings showed some correlation, considerable discordance was noted. On multivariate analysis, bridging therapy, poor performance status, and high Hematotox scores were associated with increased risk of severe early T-ICAHT. Patients with higher T-ICAHT grades showed increased platelet and red blood cell transfusion burden (p<0.001) and more bleeding events (p=0.01). T-ICAHT grades were inversely associated with overall survival (OS), with landmarked 2-year estimates ranging from 67% (G0), to 48% (G1-2) and 35% (G3+). In multivariable Cox regression analysis, the independent prognostic capacity of T-ICAHT for OS was confirmed. Finally, we validated T-ICAHT's clinical and prognostic utility in 3 external cohorts spanning an additional 599 pediatric and adult patients (NHL, MM, B-ALL), confirming its broad applicability. These findings support integrating T-ICAHT into the ICAHT framework to standardize thrombocytopenia grading in CAR-T recipients.
{"title":"T-ICAHT: Grading and Prognostic Impact of Thrombocytopenia After CAR T-cell Therapy.","authors":"Kai Rejeski,Jaime Sanz,Teng Fei,Monica S Nair,Hamza Hashmi,Abraham Avigdor,Ofrat Beyar-Katz,Veit L Bücklein,Kevin J Curran,Sigrun Einarsdottir,Jonathan H Esensten,Netta Glaubach,Noa Golan-Accav,Marina Gomez-Llobell,Iris Halamis,Orit Itzhaki,Frederick L Locke,Sham Mailankody,Ronit Marcus,Marcela V Maus,M Lia Palomba,Jae H Park,Marcelo C Pasquini,Sandeep S Raj,Sridevi Rajeeve,Gilles A Salles,Michael Scordo,Gunjan L Shah,Avichai Shimoni,Marion Subklewe,Tobias Tix,Saad Z Usmani,Ori Ben Valid,Yannis K Valtis,Tsila Zuckerman,Nirali N Shah,Miguel-Angel Perales,Roni Shouval","doi":"10.1182/blood.2025028833","DOIUrl":"https://doi.org/10.1182/blood.2025028833","url":null,"abstract":"Immune effector cell-associated hematotoxicity (ICAHT) was recently introduced as a distinct toxicity category of CAR-T therapy. While a grading system based solely on neutrophil counts was proposed (hereafter termed N-ICAHT), the prevalence and prognostic impact of thrombocytopenia remains poorly defined. In this multicenter observational study, we systematically examined patterns of thrombocytopenia in 744 patients treated with commercial CD19 CAR-T for B-cell Non-Hodgkin Lymphoma (B-NHL). We developed a grading system termed T-ICAHT with thresholds that closely aligned with N-ICAHT - based on depth, duration and timing of thrombocytopenia. In the core NHL dataset, 43% of patients developed any-grade early T-ICAHT (day 0-30), with 23% developing severe (G3+) manifestations. Late T-ICAHT (day 31-100) was observed in 42% (G3+: 13%). While T-ICAHT and N-ICAHT gradings showed some correlation, considerable discordance was noted. On multivariate analysis, bridging therapy, poor performance status, and high Hematotox scores were associated with increased risk of severe early T-ICAHT. Patients with higher T-ICAHT grades showed increased platelet and red blood cell transfusion burden (p<0.001) and more bleeding events (p=0.01). T-ICAHT grades were inversely associated with overall survival (OS), with landmarked 2-year estimates ranging from 67% (G0), to 48% (G1-2) and 35% (G3+). In multivariable Cox regression analysis, the independent prognostic capacity of T-ICAHT for OS was confirmed. Finally, we validated T-ICAHT's clinical and prognostic utility in 3 external cohorts spanning an additional 599 pediatric and adult patients (NHL, MM, B-ALL), confirming its broad applicability. These findings support integrating T-ICAHT into the ICAHT framework to standardize thrombocytopenia grading in CAR-T recipients.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"19 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143862029","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 : 2025-04-21DOI: 10.1182/blood.2025028416
Saarang R Deshpande,Hemza Tarawneh,Chloe Cate Deitelzweig,Jiayi Tong,Ting Zhou,Yong Chen,Adam Cuker
Thrombotic thrombocytopenic purpura (TTP) is a rare, potentially fatal thrombotic microangiopathy caused by severe ADAMTS13 deficiency. Prompt treatment improves survival; however, reference standard ELISA and FRETS-VWF73 ADAMTS13 activity assays have long turnaround times that necessitate empiric treatment of many patients who ultimately are found not to have TTP. Rapid assays with analytical turnaround times within one hour have recently become available. We conducted a systematic review and meta-analysis of the performance characteristics of rapid assays relative to reference standard assays for ADAMTS13 activity for patients with suspected or confirmed TTP. Nineteen studies representing three rapid ADAMTS13 assays and 4,207 patient samples were included. The HemosIL AcuStar CLIA demonstrated high sensitivity (0.98, 95% CI 0.94 - 1.00), specificity (0.99, 0.97 - 1.00), and positive (0.96, 0.90 - 0.98) and negative predictive value (0.99, 0.99 - 1.00). The Technofluor FRET and Technoscreen assays had sensitivity of 0.93 (0.86 - 0.96) and 0.98 (0.42 - 1.00), specificity of 0.98 (0.95 - 0.99) and 0.87 (0.76 - 0.94), PPV of 0.97 (0.85 - 1.00) and 0.71 (0.59 - 0.80), and NPV of 0.96 (0.93 - 0.98) and 0.99 (0.72 - 1.00), respectively. The proportion of discrepant results (relative to reference standard assays) was 0.04 (0.03 - 0.05) for HemosIL AcuStar, 0.04 (0.02 - 0.06) for Technofluor FRET, and 0.11 (0.07 - 0.16) for the Technoscreen assay. With rapid turnaround time and high sensitivity, the HemosIL AcuStar CLIA appears able to reliably avert empiric plasma exchange, corticosteroids, and caplacizumab in patients without TTP.
{"title":"Rapid ADAMTS13 activity assays for thrombotic thrombocytopenic purpura: a systematic review and meta-analysis.","authors":"Saarang R Deshpande,Hemza Tarawneh,Chloe Cate Deitelzweig,Jiayi Tong,Ting Zhou,Yong Chen,Adam Cuker","doi":"10.1182/blood.2025028416","DOIUrl":"https://doi.org/10.1182/blood.2025028416","url":null,"abstract":"Thrombotic thrombocytopenic purpura (TTP) is a rare, potentially fatal thrombotic microangiopathy caused by severe ADAMTS13 deficiency. Prompt treatment improves survival; however, reference standard ELISA and FRETS-VWF73 ADAMTS13 activity assays have long turnaround times that necessitate empiric treatment of many patients who ultimately are found not to have TTP. Rapid assays with analytical turnaround times within one hour have recently become available. We conducted a systematic review and meta-analysis of the performance characteristics of rapid assays relative to reference standard assays for ADAMTS13 activity for patients with suspected or confirmed TTP. Nineteen studies representing three rapid ADAMTS13 assays and 4,207 patient samples were included. The HemosIL AcuStar CLIA demonstrated high sensitivity (0.98, 95% CI 0.94 - 1.00), specificity (0.99, 0.97 - 1.00), and positive (0.96, 0.90 - 0.98) and negative predictive value (0.99, 0.99 - 1.00). The Technofluor FRET and Technoscreen assays had sensitivity of 0.93 (0.86 - 0.96) and 0.98 (0.42 - 1.00), specificity of 0.98 (0.95 - 0.99) and 0.87 (0.76 - 0.94), PPV of 0.97 (0.85 - 1.00) and 0.71 (0.59 - 0.80), and NPV of 0.96 (0.93 - 0.98) and 0.99 (0.72 - 1.00), respectively. The proportion of discrepant results (relative to reference standard assays) was 0.04 (0.03 - 0.05) for HemosIL AcuStar, 0.04 (0.02 - 0.06) for Technofluor FRET, and 0.11 (0.07 - 0.16) for the Technoscreen assay. With rapid turnaround time and high sensitivity, the HemosIL AcuStar CLIA appears able to reliably avert empiric plasma exchange, corticosteroids, and caplacizumab in patients without TTP.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"17 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143862037","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 : 2025-04-21DOI: 10.1182/blood.2024026936
Fangwu Wang,Laura Gonzalez,Qiuyu Lian,Colin A Hammond,Yasmine Y M Lau,Benjamin D Simons,Martin Hirst,Connie J Eaves
Recent studies indicate the human lympho-myeloid restriction process to be a different and more heterogeneous one than historically inferred. Here we describe the development of bulk and clonal culture systems that efficiently support early B-lymphoid differentiation and its use to elucidate the biological and molecular changes that accompany their initial restriction from subsets of CD34+ human cord blood cells with lympho-myeloid-limited potential. Analyses of these changes revealed that the acquisition of B-lymphoid- and neutrophil/monocyte (NM)-restricted properties are accompanied by a concomitantly accelerated and lineage-shared cell cycling activity and loss of self-renewal potential. Single-cell transcriptome analysis identified reduced expression of multiple self-renewal-associated genes and an accompanying heterogeneous activation of lineage-regulatory modules during the production of B, NM and dendritic cell precursors. By applying a novel culture system that supports early human lymphoid differentiation, we uncover a shared mechanism of proliferation control, along with persistent biological and transcriptional heterogeneity in cells undergoing B and NM lineage restriction.
最近的研究表明，人类淋巴-骨髓限制过程与历史上推断的不同，而且更加异质。在这里，我们描述了可有效支持早期 B 淋巴细胞分化的体细胞和克隆培养系统的开发过程，以及利用该系统阐明了伴随着从具有淋巴-髓系限制潜能的 CD34+ 人类脐带血细胞亚群中初步限制 B 淋巴细胞分化的生物和分子变化。对这些变化的分析表明，B淋巴细胞和中性粒细胞/单核细胞（NM）受限特性的获得伴随着细胞周期活动的加速和品系共享以及自我更新潜力的丧失。单细胞转录组分析发现，在 B 细胞、NM 细胞和树突状细胞前体的产生过程中，多个自我更新相关基因的表达减少，并伴随着系谱调控模块的异质性激活。通过应用支持人类早期淋巴细胞分化的新型培养系统，我们发现了一种共享的增殖控制机制，以及在经历 B 和 NM 系限制的细胞中持续存在的生物学和转录异质性。
{"title":"Coordinated regulation of self-renewal and cell cycle during human lympho-myeloid lineage restriction.","authors":"Fangwu Wang,Laura Gonzalez,Qiuyu Lian,Colin A Hammond,Yasmine Y M Lau,Benjamin D Simons,Martin Hirst,Connie J Eaves","doi":"10.1182/blood.2024026936","DOIUrl":"https://doi.org/10.1182/blood.2024026936","url":null,"abstract":"Recent studies indicate the human lympho-myeloid restriction process to be a different and more heterogeneous one than historically inferred. Here we describe the development of bulk and clonal culture systems that efficiently support early B-lymphoid differentiation and its use to elucidate the biological and molecular changes that accompany their initial restriction from subsets of CD34+ human cord blood cells with lympho-myeloid-limited potential. Analyses of these changes revealed that the acquisition of B-lymphoid- and neutrophil/monocyte (NM)-restricted properties are accompanied by a concomitantly accelerated and lineage-shared cell cycling activity and loss of self-renewal potential. Single-cell transcriptome analysis identified reduced expression of multiple self-renewal-associated genes and an accompanying heterogeneous activation of lineage-regulatory modules during the production of B, NM and dendritic cell precursors. By applying a novel culture system that supports early human lymphoid differentiation, we uncover a shared mechanism of proliferation control, along with persistent biological and transcriptional heterogeneity in cells undergoing B and NM lineage restriction.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"37 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143862025","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 : 2025-04-17DOI: 10.1182/blood.2025028401
Jason Gotlib
{"title":"Introduction to a How I Treat series on myeloproliferative neoplasms.","authors":"Jason Gotlib","doi":"10.1182/blood.2025028401","DOIUrl":"https://doi.org/10.1182/blood.2025028401","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"22 1","pages":"1707-1709"},"PeriodicalIF":20.3,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143846346","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 : 2025-04-17DOI: 10.1182/blood.2024027324
Jerome Moreaux
{"title":"Dual targeting of EZH2 and DOT1L in DLBCL.","authors":"Jerome Moreaux","doi":"10.1182/blood.2024027324","DOIUrl":"https://doi.org/10.1182/blood.2024027324","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"40 1","pages":"1714-1715"},"PeriodicalIF":20.3,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143846343","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 : 2025-04-17DOI: 10.1182/blood.2024028274
Natalie S Grover,Barbara Savoldo
{"title":"Can less differentiation drive CARs to success?","authors":"Natalie S Grover,Barbara Savoldo","doi":"10.1182/blood.2024028274","DOIUrl":"https://doi.org/10.1182/blood.2024028274","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"90 1","pages":"1712-1713"},"PeriodicalIF":20.3,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143846344","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 : 2025-04-17DOI: 10.1182/blood.2024028020
Soma Roy Chakraborty,Jeremiah X Karrs
{"title":"A rare case of nodal hairy cell leukemia exhibiting characteristic morphological and immunohistochemical features.","authors":"Soma Roy Chakraborty,Jeremiah X Karrs","doi":"10.1182/blood.2024028020","DOIUrl":"https://doi.org/10.1182/blood.2024028020","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"17 1","pages":"1826"},"PeriodicalIF":20.3,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143846299","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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