Blood最新文献

{"title":"A small B-cell leukemia/lymphoma with weak to negative expression of CD5.","authors":"Shamini Selvarajah, Daniel Xia","doi":"10.1182/blood.2025028974","DOIUrl":"https://doi.org/10.1182/blood.2025028974","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"145 24","pages":"2931"},"PeriodicalIF":21.0,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144274217","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":"Deficiency of T follicular helper cell Tet3 DNA demethylation inhibits pathogenic IgG2c class switching and chronic GVHD.","authors":"Michael C Zaiken, Sujeong Jin, Cameron S McDonald-Hyman, Christina R Hartigan, Peter T Sage, Keli L Hippen, Brent H Koehn, Angela Panoskaltsis-Mortari, Megan J Riddle, Cindy R Eide, Jakub Tolar, Geoffrey R Hill, Leo Luznik, Corey S Cutler, Jerome R Ritz, Leslie S Kean, Ageliki Tsagaratou, Anjana Rao, Bruce R Blazar","doi":"10.1182/blood.2024025036","DOIUrl":"10.1182/blood.2024025036","url":null,"abstract":"<p><strong>Abstract: </strong>Chronic graft-versus-host disease (cGVHD) is the leading cause of morbidity and nonrelapse-associated mortality after allogeneic hematopoietic cell transplantation. Treating steroid resistant/refractory cGVHD remains challenging. Epigenetic regulators can have global transcriptional effects that control donor T-cell responses. We previously showed that inhibiting histone lysine motifs by chromatin-modifying enzymes can ameliorate murine cGVHD. Targeting donor T-cell DNA methyltransferases reduce acute GVHD. In this study, we sought to investigate the DNA demethylase ten-eleven translocase (Tet) methylcytosine dioxygenases 2 (Tet2) and 3 (Tet3) in T follicular helper cell (TFH)-dependent cGVHD. In a clinically relevant model of cGVHD that recapitulates pulmonary fibrosis from bronchiolitis obliterans, recipients of Tet2-deleted donor T cells did not have improved pulmonary function tests in contrast with the markedly improved pulmonary function in Tet3-deleted donor T cells. Tet3 deleted donor T cells did not impair TFH-dependent germinal center (GC) formation. Unexpectedly, TET3 deficiency led to elevated GATA3 (GATA-binding protein 3) expression in and interleukin-4 production by TFHs. TET3-deficient TFHs supported GC B-cell immunoglobulin (Ig) class switching to nonpathogenic IgG1 but not pathogenic IgG2c, thereby enabling mice to escape cGVHD pulmonary fibrosis. Elevated GATA3 expression and disruption of IgG2c class switching was recapitulated in an in vitro human GC culture system. These studies provide new insights into the function of Tet3 in TFH-driven immunoglobulin class switching and suggest a new approach to mitigate cGVHD.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"2813-2827"},"PeriodicalIF":21.0,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143122257","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":"Comparison of the safety profiles of CD19-targeting CAR T-cell therapy in patients with SLE and B-cell lymphoma.","authors":"Fabian Müller, Nora Rebecca Schwingen, Melanie Hagen, Julia Katharina Scholz, Michael Aigner, Andreas Wirsching, Jule Taubmann, Sascha Kretschmann, Soraya Kharboutli, Tobias Krickau, Nora Naumann-Bartsch, Giulia Benintende, Silvia Spoerl, Tobias Rothe, Heiko Bruns, Ricardo Grieshaber-Bouyer, Markus Metzler, David B Blumenthal, Frederik Graw, Georg Schett, Andreas Mackensen, Simon Völkl","doi":"10.1182/blood.2025028375","DOIUrl":"https://doi.org/10.1182/blood.2025028375","url":null,"abstract":"<p><p>CD19-directed chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of relapsed/refractory B-cell non-Hodgkin lymphoma (B-NHL) and recently showed effects in autoimmune diseases such as systemic lupus erythematosus (SLE). Despite high levels of inflammation, toxicity appeared to differ in SLE and B-NHL. We therefore compared CAR T-cell kinetics and treatment-related side-effects to better define the distinct toxicity profiles. Contrary to similar CAR T-cell expansion, SLE patients revealed lower incidence and severity of cytokine-release syndrome, immune-effector cell-associated neurotoxicity syndrome, and immune-effector cell-associated hematotoxicity. While neutrophil nadir was lower in SLE patients after therapy, platelets remained close to normal and hematotoxicity was shorter in SLE than in B-NHL. Reduced hematotoxicity correlated with lower acute phase inflammation, better hematological reserve prior to CAR T-cell therapy, and distinct serum cytokine profiles. Interestingly, CAR T-cell persistence was consistently shorter and reconstitution of conventional T- and B-cells was faster in SLE. In both cohorts, B-cell reconstitution correlated with functional CD4+ T-cell recovery, indicating a general biological process of hematopoietic and immune system regeneration. In summary, similar lymphodepletion and CAR T-cell pharmacokinetics resulted in distinct toxicity, demonstrating a favorable side effect profile of CAR T-cell therapy in SLE including faster recovery of the adaptive immune system.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144282368","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":"The fit older adult with acute myeloid leukemia: clinical challenges to providing evidence-based frontline treatment.","authors":"Sameem Abedin, Geoffrey L Uy, Laura C Michaelis","doi":"10.1182/blood.2024026004","DOIUrl":"10.1182/blood.2024026004","url":null,"abstract":"<p><strong>Abstract: </strong>Recent advances in acute myeloid leukemia (AML) come from studies investigating older adults aged <60 years, those aged ≥75 years, or less fit adults. Uncertainty exists for the management of otherwise healthy adults with AML in their 60s and 70s, which also represents a significant proportion of AML cases. We discuss current considerations in older, fit adults with AML, including determination of fitness, factors beyond fitness that should be assessed, and challenges and innovations to improve patient outcomes.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"2840-2846"},"PeriodicalIF":21.0,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143031930","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":"Surface pTα expression predicts LCK activation and preclinical synergy of LCK and JAK coinhibition in adult T-ALL.","authors":"Lucien Courtois, Antoine Pinton, Aurélie Cabannes-Hamy, Mathieu Simonin, Guillaume P Andrieu, Mélodie Queri, Charlotte Smith, Guillaume Charbonnier, Marie-Emilie Dourthe, Marianne Courgeon, Grégoire Huré, Nicolas Gaidot, Elizabeth Macintyre, Hervé Dombret, André Baruchel, Nicolas Boissel, Aurore Touzart, Ludovic Lhermitte, Philippe Rousselot, Vahid Asnafi","doi":"10.1182/blood.2024027982","DOIUrl":"10.1182/blood.2024027982","url":null,"abstract":"<p><strong>Abstract: </strong>Refractory and/or relapsing T-cell acute lymphoblastic leukemia (T-ALL) remains a major therapeutic challenge. The pre-T-cell receptor (TCR) pathway has recently emerged as a therapeutic target via LCK inhibition in this context. However, there is a need for simple and quickly assessable biomarkers to predict sensitivity to LCK inhibitors. Moreover, targeting LCK alone by tyrosine kinase inhibitors, such as dasatinib, often results in transient clinical responses, emphasizing the need for efficient combination strategies. Here, we assessed pre-TCR α chain (pTα) surface expression by flow cytometry in a unique series of 50 adult T-ALL patient-derived xenografts (PDXs). We show that cases displaying a cortical phenotype often express high levels of surface pTα (pre-TCR+ T-ALL) and that the latter associates with LCK activation. Furthermore, we show that ectopic interleukin-7 receptor (IL-7R) expression can rescue pre-TCR+ T-ALL from dasatinib cytotoxicity (5 PDXs). We tested whether coinhibition of pre-TCR and IL-7R signaling pathways could be synergetic in pre-TCR+ IL-7R+ T-ALL (11 PDXs). Combination of JAK inhibitors, ruxolitinib or tofacitinib, with dasatinib elicited strong and specific synergy in IL-7R+ pre-TCR+ T-ALL in vitro, including in the relapse setting (4 of 28 patient-derived primary samples). Using 3 adult-PDX models, we show that in vivo treatment with this combination significantly delayed leukemic progression and prolonged survival compared with either monotherapy. This preclinical study thus proposes the use of pTα as a biomarker of LCK-inhibitor sensitivity in T-ALL, and suggests that dual targeting of IL-7R and pre-TCR signaling pathways may be a relevant therapeutic strategy in a substantial proportion of adult T-ALL.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"2903-2913"},"PeriodicalIF":21.0,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143466939","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":"NOTCH1 dimeric signaling is essential for T-cell leukemogenesis and leukemia maintenance.","authors":"Francesco Tamiro, Costanzo Padovano, Elisabetta De Santis, Serena Di Iasio, Delia Francesca Sansico, Valentina Canistro, Mattia Colucci, Chiara Di Nunzio, Gaja Bruno, Kashish Doshi, Angela Totaro, Eric Gu, Michele Santodirocco, Andrew P Weng, Vincenzo Giambra","doi":"10.1182/blood.2024027020","DOIUrl":"10.1182/blood.2024027020","url":null,"abstract":"<p><strong>Abstract: </strong>T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy that is characterized by an expansion of T-cell progenitors and DNA mutations that lead to overactive NOTCH1 signaling in >50% of T-ALL cases. Using synthetic models of human T-ALL, we report that NOTCH1 dimeric signaling was crucial for the leukemogenesis of human hematopoietic stem/progenitor cells (HSPCs) from cord blood. We also identified a Notch dimerization-dependent gene signature, including the HES4 transcription factor, which induced a proliferative advantage in human HSPCs and in Notch dimerization-dependent, patient-derived xenografts of T-ALL. Interestingly, in human T-ALL cells, HES4 enforced the expression of the Δ133p53 isoform with the concomitant block of proapoptotic p53 target genes and the induction of BCL2L1 gene expression and antiapoptotic B-cell lymphoma extra-large protein. In addition, through an integrated experimental approach that included genetically modified cell lines, RNA/chromatin immunoprecipitation sequencing, and single-cell RNA sequencing profiles of primary T-ALL samples, we revealed cell subsets with Notch dimerization-dependent gene signatures, which indirectly correlated with proapoptotic genes and directly associated with cell markers of poor clinical outcome in primary T-ALL samples. Taken together, these findings highlight the crucial role of NOTCH1 dimeric signaling in human T-cell leukemogenesis and T-ALL maintenance, suggesting that a possible benefit can be obtained with a therapeutic strategy that target NOTCH1 dimer signaling or its downstream effectors.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"2887-2902"},"PeriodicalIF":21.0,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143514607","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":"RhoA GAP Myo9b regulates β2-integrin activity and neutrophil recruitment during murine acute kidney injury.","authors":"Anika Cappenberg, Marina Oguama, Mathis Richter, Andreas Margraf, Wida Amini, Pia Lindental, Sina Mersmann, Bernadette Bardel, Helena Block, Thomas Vogl, Oliver Soehnlein, Klaus Ley, Jan Rossaint, Alexander Zarbock","doi":"10.1182/blood.2024027583","DOIUrl":"https://doi.org/10.1182/blood.2024027583","url":null,"abstract":"<p><p>An acute inflammatory response to infection or sterile injury involves an adequate activation and recruitment of leukocytes. Activation of β2-integrins is required for neutrophil recruitment and is also mandatory for various neutrophil cell-intrinsic functions. GTPases are key regulators of the actin cytoskeleton and are required for β2-integrin activation. MyosinIXb (Myo9b), a Rho GTPase-activating protein, is essential for regulating Rho activity in neutrophils. Yet, the exact molecular mechanism how Myo9b regulates β2-integrin activity and neutrophil recruitment into inflamed tissue is unknown. We demonstrate that Myo9b deficiency causes RhoA overactivation, increases actin cytoskeleton rearrangement in neutrophils, decreases neutrophil recruitment into the kidney and improves kidney function in murine models of acute kidney injury. Loss of Myo9b also affects neutrophil effector functions and causes increased rolling velocity, decreased adhesion, impaired crawling, and strongly reduced transmigration of neutrophils in vivo. Mechanistically, Myo9b regulates RhoA activity which is required for chemokine- and selectin-induced talin-1 recruitment to β2-integrins. Thus, Myo9b is a crucial regulator of important signaling pathways in neutrophils and is required for an adequate immune response triggered by chemokines and selectins.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144282370","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":"Sickle cell disease and diabetes mellitus.","authors":"Pablo Bartolucci","doi":"10.1182/blood.2025029120","DOIUrl":"https://doi.org/10.1182/blood.2025029120","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"145 24","pages":"2812"},"PeriodicalIF":21.0,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144274223","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":"Safety and efficacy of rilzabrutinib vs placebo in adults with immune thrombocytopenia: the phase 3 LUNA3 study.","authors":"David J Kuter, Waleed Ghanima, Nichola Cooper, Howard A Liebman, Lei Zhang, Yu Hu, Yoshitaka Miyakawa, Wojciech Homenda, Luisa Elena Morales Galindo, Ana Lisa Basquiera, Chuen Wen Tan, Guray Saydam, Marie Luise Hütter-Krönke, Chatree Chai-Adisaksopha, David Gómez-Almaguer, Huy Tran, Ho-Jin Shin, Ademar Dantas da Cunha Junior, Zsolt Lazar, Cristina Pascual Izquierdo, Ilya Kirgner, Elisa Lucchini, Ganna Kuzmina, Michael Fillitz, Sylvain Audia, Minakshi Taparia, Matias Cordoba, Remco Diab, Mengjie Yao, Imene Gouia, Michelle Lee, Ahmed Daak","doi":"10.1182/blood.2024027336","DOIUrl":"10.1182/blood.2024027336","url":null,"abstract":"<p><strong>Abstract: </strong>Rilzabrutinib is a covalent, reversible Bruton tyrosine kinase inhibitor targeting multiple immune thrombocytopenia (ITP)-related mechanisms. The phase 3 LUNA3 study in previously treated adults with persistent/chronic ITP evaluated oral rilzabrutinib 400 mg twice daily (n = 133) vs placebo (n = 69) for 24 weeks. At baseline overall, median age was 47 years, 63% female, 7.7 year median ITP duration, and 28% prior splenectomy. Overall (N = 202), 85 (64%) rilzabrutinib and 22 (32%) placebo patients achieved platelet response (≥50 × 109/L or 30 × 109/L to <50 × 109/L and doubled from baseline) during the first 12 weeks and were eligible to continue. The primary end point, durable platelet response (platelet count ≥50 × 109/L for ≥two-thirds of ≥8 of the last 12 of 24 weeks without rescue therapy), was observed in 31 (23%) rilzabrutinib vs 0 placebo patients (P < .0001). All secondary efficacy end points were significantly superior for rilzabrutinib (P < .05). Median time to first platelet response was 15 days in rilzabrutinib responders. Rilzabrutinib significantly reduced rescue therapy use by 52% (P = .0007) and improved week 25 bleeding scores (P = .0006). Improved physical fatigue was sustained from week 13 (P = .01) through 25 (P = .0003). Treatment-related adverse events were mainly grade 1/2. One rilzabrutinib patient with multiple risk factors had serious treatment-related grade 3 peripheral embolism (lower left leg), and another died from unrelated pneumonia. Rilzabrutinib in patients who failed multiple previous ITP therapies showed rapid and durable platelet response, reduced rescue medication and bleeding, improved physical fatigue, and favorable safety. Trial registration: www.clinicaltrials.gov (#NCT04562766) and www.clinicaltrialsregister.eu (#2020-002063-60).</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"2914-2926"},"PeriodicalIF":21.0,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143639667","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 single dose of a CD137 antibody-drug conjugate protects nonhuman primate allogeneic HCT recipients against acute GVHD.","authors":"Ulrike Gerdemann, Kyle Kimler, Matthew R Warren, Connor McGuckin, Ryan A Fleming, Matthew R D'Ambra, Alal Eran, Alexandre Albanese, Edward Chen, Marlana B Winschel, Lorenzo Cagnin, Jennifer Lane, Lev Gorfinkel, Bartley W Adams, Jean Kwun, Leanne Lanieri, Megan D Hoban, Tahirih L Lamothe, Sharon L Hyzy, Lisa M Olson, Angela Panoskaltsis-Mortari, Susan E Prockop, Bruce R Blazar, Leslie S Kean, Victor Tkachev","doi":"10.1182/blood.2024027239","DOIUrl":"https://doi.org/10.1182/blood.2024027239","url":null,"abstract":"<p><p>Rapid CD137 upregulation on alloreactive T-cells upon allogeneic stimulation suggests that their selective elimination could prevent acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (HCT). Here, we developed a novel aGVHD prophylactic regimen consisting of a single dose of an anti-CD137 antibody-drug conjugate (CD137-ADC) administered on the day of transplant without additional immunosuppression. The CD137-ADC depleted both human and non-human primate (NHP) activated T-cells and proved highly effective in preventing xenogeneic aGVHD in mice receiving human peripheral blood mononuclear cells (PBMC), as well as in NHP undergoing MHC-haploidentical HCT. Flow cytometry analysis of NHP T-cells indicated specific depletion of activated PD-1+ CD4 and CD8 T-cells, while sparing naïve and PD-1-OX40+ memory T-cell subsets during the first week after HCT. CD137-ADC-treated NHP recipients demonstrated robust hematopoietic and immune reconstitution. Hallmarks of T-cell recovery after CD137-ADC, which were associated with long-term aGVHD-free survival, included reconstitution of CD4 memory T-cells expressing TRAIL, terminally-differentiated CD8 T-cells expressing CX3CR1, and CD4 FoxP3+ Tregs - cell types not expected to be involved in aGVHD pathogenesis. CD137-ADC-treated recipients demonstrated a higher risk of reactivation of rhLCV (the rhesus macaque EBV analogue), which was associated with reconstitution of follicular helper T-cells, interferon signaling-associated memory, and gamma-delta T-cell subsets. This reactivation was controllable with rituximab administration. These results document effective depletion of alloreactive T-cells and prevention of aGVHD following a single dose of CD137-ADC, suggesting that clinical translation should be carefully explored.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144282367","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}