Blood最新文献_第6页

TTP: a disorder for all physicians. TTP：所有医生的疾病。

IF 20.3 1区医学

Blood Pub Date : 2025-07-10 DOI: 10.1182/blood.2025029525

James N George

引用次数: 0

When increased bone marrow blasts may not mean malignancy. 当骨髓母细胞增多时，可能并不意味着恶性肿瘤。

IF 20.3 1区医学

Blood Pub Date : 2025-07-10 DOI: 10.1182/blood.2025029542

Carlo Zaninetti,Alessandro Pecci

引用次数: 0

Iron overload in HFE-related hemochromatosis severely impairs Vδ2+ γδ T-cell homeostasis. 高铁相关性血色素沉着症患者铁超载严重损害Vδ2 γδ t细胞稳态。

IF 21 1区医学

Blood Pub Date : 2025-07-10 DOI: 10.1182/blood.2024025345

Derya Erdogdu, Ina Becoku, Valerie Huber, Yao Wang, Matthias Eyrich, Hisayoshi Hashimoto, Michaela Döring, Johannes Schulte, Karin Schilbach

{"title":"Iron overload in HFE-related hemochromatosis severely impairs Vδ2+ γδ T-cell homeostasis.","authors":"Derya Erdogdu, Ina Becoku, Valerie Huber, Yao Wang, Matthias Eyrich, Hisayoshi Hashimoto, Michaela Döring, Johannes Schulte, Karin Schilbach","doi":"10.1182/blood.2024025345","DOIUrl":"10.1182/blood.2024025345","url":null,"abstract":"Abstract: HFE-related hemochromatosis induces systemic iron overload. Although extensive studies indicate a pivotal role for iron homeostasis in αβ T-cell immunity, its effect on γδ T cells is unknown. Here, we found a reversal of the Vδ2+/Vδ2- ratio in the γδ T-cell compartment as a feature of hemochromatosis, which is associated with a Vδ2+ population that cannot be enriched by zoledronic acid (ZOL) stimulation, despite evidence of T-cell receptor (TCR)-ligand formation and strong proliferative behavior. In vivo, reactive oxygen species (ROS) production and exhaustion marker expression are significantly increased on Vδ2+ T cells in hemochromatosis compared with healthy individuals. Ex vivo, hemochromatosis donor-derived Vδ2+ cells are hyporesponsive to TCR stimulation in terms of ROS production but significantly increase their paramount expression of exhaustion markers. Fas-Fas ligand coexpression indicates their high susceptibility to activation-induced cell death. Consistent therewith, FeSO4 alone induces Vδ2+ subset-specific proliferation in healthy peripheral blood mononuclear cells comparable to stimulation by ZOL, and blocking experiments identify FeSO4-induced proliferation as BTN3A1/TCR mediated. Pyrophosphate is key for Vδ2+-TCR ligand formation. Iron, by suppressing pyrophosphatase alkaline phosphatase, promotes their stability. Therefore, our data suggest that the transcriptional repression of pyrophosphatases, as under the conditions of iron overload in hemochromatosis in vivo, leads to the constitutive availability of stress-signaling Vδ2+-TCR ligand and permanent TCR triggering in Vδ2+ T cells even under homeostatic conditions, which ultimately results in their subset-specific, activation-induced cell death. A similar phenotype was observed in patients with iron overload due to inborn hemoglobinopathies, suggesting an inverted Vδ2+/Vδ2- ratio in the γδ T-cell compartment as a hallmark of iron overload.","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"219-232"},"PeriodicalIF":21.0,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751131","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

Blunted CD40-responsive enhancer activation in CREBBP-mutant lymphomas can be restored by enforced CD4 T-cell engagement. 在CREBBP突变淋巴瘤中，CD40反应增强子活化的缺陷可通过加强CD4 T细胞参与而得到恢复。

IF 21 1区医学

Blood Pub Date : 2025-07-10 DOI: 10.1182/blood.2024026664

Haopeng Yang, Wenchao Zhang, Vida Ravanmehr, Guiling Cui, Kevin Bowman, Ruidong Chen, Jared M Henderson, Shyanne Lockman, Estela Rojas, Ashley Wilson, Sydney Parsons, Ariel Mechaly, Leslie Regad, Ahmed Haouz, Christopher R Flowers, Sattva Neelapu, Loretta Nastoupil, R Eric Davis, Qing Deng, Fernando Rodrigues-Lima, Michael R Green

{"title":"Blunted CD40-responsive enhancer activation in CREBBP-mutant lymphomas can be restored by enforced CD4 T-cell engagement.","authors":"Haopeng Yang, Wenchao Zhang, Vida Ravanmehr, Guiling Cui, Kevin Bowman, Ruidong Chen, Jared M Henderson, Shyanne Lockman, Estela Rojas, Ashley Wilson, Sydney Parsons, Ariel Mechaly, Leslie Regad, Ahmed Haouz, Christopher R Flowers, Sattva Neelapu, Loretta Nastoupil, R Eric Davis, Qing Deng, Fernando Rodrigues-Lima, Michael R Green","doi":"10.1182/blood.2024026664","DOIUrl":"10.1182/blood.2024026664","url":null,"abstract":"Abstract: The CREBBP lysine acetyltransferase (KAT) is frequently mutated in follicular lymphoma and diffuse large B-cell lymphoma and has been studied using gene knockout in murine and human cells. However, most CREBBP mutations encode amino acid substitutions within the catalytic KAT domain (CREBBP KAT-PM) that retain an inactive protein and have not been extensively characterized. Using CRISPR gene editing and extensive epigenomic characterization of lymphoma cell lines, we found that CREBBP KAT-PM lead to unloading of CREBBP from chromatin, loss of enhancer acetylation, and prevention of EP300 compensation. These enhancers were enriched for those that are dynamically loaded by CREBBP in the normal centroblast-to-centrocyte transition in the germinal center, including enhancers activated in response to CD40 signaling, leading to blunted molecular response to CD40 ligand in lymphoma cells. We provide evidence that CREBBP KAT-PM inhibits EP300 function by binding limiting quantities nuclear transcription factor (TF), thereby preventing its compensatory activity. This effect can be experimentally overcome by expressing saturating quantities of TF or biologically attenuated by strong stimulation of CD40 signaling that increases nuclear TF abundance. Importantly, epigenetic responses to CD40 signaling can be induced by enforcing CD4 T-cell engagement using a bispecific antibody, leading to CD40-dependent restoration of antigen presentation machinery in CREBBP KAT-PM cells and cell death. Therefore, we provide a mechanistic basis for enhancer deregulation by CREBBP KAT-PM and highlight enforced CD4 T-cell engagement as a potential approach for overcoming these effects.","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"191-205"},"PeriodicalIF":21.0,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143639636","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

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IF 20.3 1区医学

Blood Pub Date : 2025-07-10 DOI: 10.1016/s0006-4971(25)01477-6

引用次数: 0

Efficacy of combined CD38 and PD-1 inhibition with isatuximab and cemiplimab for relapsed/refractory NK/T-cell lymphoma. 依沙妥昔单抗和西米单抗联合抑制复发/难治性NK/ t细胞淋巴瘤CD38和PD1的疗效

IF 21 1区医学

Blood Pub Date : 2025-07-10 DOI: 10.1182/blood.2024027109

Seok Jin Kim, Jing Quan Lim, Sang Eun Yoon, Deok-Hwan Yang, Ji Hyun Lee, Sung Yong Oh, Yoon Seok Choi, Seong Hyun Jeong, Min Kyoung Kim, Sung Nam Lim, Junhun Cho, Bon Park, Kyung Ju Ryu, Seunghyun Choi, Yoon Park, Kerry May Huifen Lim, Nur Ayuni Binte Muhammad Taib, Choon Kiat Ong, Soon Thye Lim, Won Seog Kim

{"title":"Efficacy of combined CD38 and PD-1 inhibition with isatuximab and cemiplimab for relapsed/refractory NK/T-cell lymphoma.","authors":"Seok Jin Kim, Jing Quan Lim, Sang Eun Yoon, Deok-Hwan Yang, Ji Hyun Lee, Sung Yong Oh, Yoon Seok Choi, Seong Hyun Jeong, Min Kyoung Kim, Sung Nam Lim, Junhun Cho, Bon Park, Kyung Ju Ryu, Seunghyun Choi, Yoon Park, Kerry May Huifen Lim, Nur Ayuni Binte Muhammad Taib, Choon Kiat Ong, Soon Thye Lim, Won Seog Kim","doi":"10.1182/blood.2024027109","DOIUrl":"10.1182/blood.2024027109","url":null,"abstract":"Abstract: This study aimed to assess the efficacy and safety of combining cemiplimab, an anti-programmed cell death protein 1 (PD-1) antibody, with isatuximab, an anti-CD38 antibody, in relapsed or refractory extranodal natural killer/T-cell lymphoma (R/R ENKTL). The hypothesis was that CD38 blockade could enhance the antitumor activity of PD-1 inhibitors. Eligible patients received cemiplimab (250 mg on days 1 and 15) and isatuximab (10 mg/kg on days 2 and 16) IV every 4 weeks for 6 cycles. Responders then received cemiplimab (350 mg) and isatuximab (10 mg/kg) every 3 weeks for up to 24 months. The primary end point was the complete response (CR) rate based on the best response. Of 37 patients enrolled, the CR rate was 51% (19/37), exceeding the primary end point of 40%, and the objective response rate was 65% (24/37). After a median follow-up of 30.2 months (95% confidence interval [CI], 25.6-34.8 months), the median progression-free survival was 9.5 months (95% CI, 1.4-17.6 months), whereas the median overall survival had not yet been reached. Patients achieving CR received a median of 28 cycles (range, 4-33 cycles), and the median duration of response for responders (n = 24) was 29.4 months (95% CI, 15.4-43.4 months). Structural variations disrupting the 3'-untranslated region of PD-L1 and high programmed death ligand 1 (PD-L1) expression were observed in responders. Most adverse events were mild (grade 1-2), with grade ≥3 events (32%) and no treatment-related deaths. The combination of isatuximab and cemiplimab demonstrated sustained antitumor activity and a manageable safety profile in R/R ENKTL. This phase 2 trial is registered at www.clinicaltrials.gov as number NCT04763616.","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"155-166"},"PeriodicalIF":21.0,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143613293","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

Redefining risk stratification in pLCH. 重新定义pLCH的风险分层。

IF 21 1区医学

Blood Pub Date : 2025-07-10 DOI: 10.1182/blood.2025029134

Jithma P Abeykoon, W Oliver Tobin

引用次数: 0

Thrombocytopenia in myelofibrosis is characterized by inflammatory megakaryocytes with reduced G6B expression. 骨髓纤维化中血小板减少的特征是炎性巨核细胞G6B表达降低。

IF 20.3 1区医学

Blood Pub Date : 2025-07-10 DOI: 10.1182/blood.2024027363

Lilian Varricchio,Gohar Mosoyan,Sebastian El Ghaity-Beckley,Md Babu Mia,Shivani Handa,Christian Salib,John O Mascarenhas,Ronald Hoffman

{"title":"Thrombocytopenia in myelofibrosis is characterized by inflammatory megakaryocytes with reduced G6B expression.","authors":"Lilian Varricchio,Gohar Mosoyan,Sebastian El Ghaity-Beckley,Md Babu Mia,Shivani Handa,Christian Salib,John O Mascarenhas,Ronald Hoffman","doi":"10.1182/blood.2024027363","DOIUrl":"https://doi.org/10.1182/blood.2024027363","url":null,"abstract":"The megakaryocytic (MK) specific immunoreceptor G6b-B plays an essential role in MK development. Since germline loss-of-function mutations of G6b-B in man and its deletion in mouse models leads to thrombocytopenia and a myelofibrosis-like clinical phenotype (MF-MPIG6B), we explored the role of G6b-B in patients with MF due to a myeloproliferative neoplasm (MPN) with thrombocytopenia (MPN-MF-T). We demonstrated that MKs generated from mononuclear cells (MNCs) from a patient with MF-MPIG6B as well as patients with MPN-MF-T, failed to express GATA1 and G6B and possessed a protein pattern expression characteristic of MKs primed for inflammation rather than platelet production. MNCs from MPN-MF-T patients also generated fewer MK biased hematopoietic stem cells (HSCs) and greater numbers of small cytoplasmic immature MKs (CD41+CD42-G6B-) as compared to MNCs from non-thrombocytopenic MPN-MF patients (MPN-MF-NT). Plasma levels of TGFβ1 and YKL-40 which were shown to arrest normal MK maturation were elevated in the MF-MPIG6B patient. Although TGFβ1 plasma levels were similarly elevated in MPN-MF-T and MPN-MF-NT patients, TNFα and YKL-40 levels were upregulated to a greater extent in MPN-MF-T than MPN-MF-NT patients. Moreover, we identified a reciprocal positive regulatory loop involving TGFβ1 and YKL-40 in MF MKs. These findings indicate that impaired MK maturation, and reduced G6B expression lead to the predominance of pro-inflammatory MKs which produce factors that further arrest MK development in MF-MPIG6B and MPN-MF-T patients. NCT03895112.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"13 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144603915","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

Boosting CAR T-Cell Efficacy by Blocking Proteasomal Degradation of Membrane Antigens. 阻断膜抗原蛋白酶体降解提高CAR - t细胞疗效。

IF 20.3 1区医学

Blood Pub Date : 2025-07-10 DOI: 10.1182/blood.2024027616

Leonie Rieger,Kilian Irlinger,Franziska Füchsl,Marlene Tietje,Anna Purcarea,Nicolas Mathis Barbian,Melanie Faber,Carolin Vogelsang,Lisa Pfeuffer,Sonja Stotz,Oleksandra Karpiuk,Tobias Schulze,Abirami Augsburger,Nadine Glaisner,Verena Konetzki,Sabrina Friedel,Andrej Besse,Lenka Besse,Christoph Driessen,Maike Buchner,Kristina Schwamborn,Katja Steiger,Piero Giansanti,Sebastian Theurich,Johannes M Waldschmidt,Klaus Martin Kortüm,Michael Hudecek,Hermann Einsele,Marion Högner,Bernhard Kuster,Angela Krackhardt,Judith S Hecker,Florian Bassermann

{"title":"Boosting CAR T-Cell Efficacy by Blocking Proteasomal Degradation of Membrane Antigens.","authors":"Leonie Rieger,Kilian Irlinger,Franziska Füchsl,Marlene Tietje,Anna Purcarea,Nicolas Mathis Barbian,Melanie Faber,Carolin Vogelsang,Lisa Pfeuffer,Sonja Stotz,Oleksandra Karpiuk,Tobias Schulze,Abirami Augsburger,Nadine Glaisner,Verena Konetzki,Sabrina Friedel,Andrej Besse,Lenka Besse,Christoph Driessen,Maike Buchner,Kristina Schwamborn,Katja Steiger,Piero Giansanti,Sebastian Theurich,Johannes M Waldschmidt,Klaus Martin Kortüm,Michael Hudecek,Hermann Einsele,Marion Högner,Bernhard Kuster,Angela Krackhardt,Judith S Hecker,Florian Bassermann","doi":"10.1182/blood.2024027616","DOIUrl":"https://doi.org/10.1182/blood.2024027616","url":null,"abstract":"Chimeric antigen receptor (CAR) T cells exhibit high response rates in B cell malignancies, but most patients eventually relapse. A key mechanism of treatment failure is the loss or downregulation of tumor antigen expression, yet strategies to modulate cell surface levels of CAR T cell targets remain largely unexplored. Here we identify B cell maturation antigen (BCMA), a central CAR T cell target in multiple myeloma (MM), as a highly short-lived protein that undergoes K48-linked polyubiquitylation at the plasma membrane, leading to its p97-dependent degradation via the ubiquitin-proteasome system (UPS). This previously unprecedented mechanism of plasma membrane protein regulation enables significant enhancement of BCMA expression via proteasome inhibitors (PI). The clinically approved PI carfilzomib (CFZ) significantly enhances the efficacy of BCMA-directed CAR T cells against both PI-sensitive and refractory MM cells in vitro and in vivo. Notably, treatment of ten patients with CFZ under the compassionate use CarCAR protocol - after relapse following BCMA CAR T cell therapy - resulted in increased BCMA expression in all patients. However, clinical responses were observed only in those with residual and/or expanding CAR T cells, suggesting restored CAR T cell function. These findings provide a rationale for the use of CFZ treatment in relapsed or refractory MM following BCMA CAR T therapy, advocate for future trials combining CFZ with BCMA CAR T cells and provide a framework for exploring UPS-dependent degradation of other immunotherapy antigens.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"109 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144603962","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

Genetic and epigenetic mechanisms of GPRC5D loss after anti-GPRC5D CAR T-cell therapy in multiple myeloma. 多发性骨髓瘤患者接受抗 GPRC5D CAR T 细胞疗法后 GPRC5D 丢失的遗传和表观遗传机制。

IF 21 1区医学

Blood Pub Date : 2025-07-10 DOI: 10.1182/blood.2024026622

Sha Ma, Jieyun Xia, Miao Zhang, Wenyu Li, Meng Xiao, Yuqian Sha, Wenya Wang, Jianteng Zhou, Ying Wang, Kunming Qi, Chunling Fu, Zengtian Sun, Dian Zhou, Qian Sun, Tingting Qiu, Zhiling Yan, Feng Zhu, Wei Chen, Hai Cheng, Wei Sang, Jiang Cao, Depeng Li, Zhenyu Li, Mariateresa Fulciniti, Yao Yao, Kailin Xu, Mingshan Niu

{"title":"Genetic and epigenetic mechanisms of GPRC5D loss after anti-GPRC5D CAR T-cell therapy in multiple myeloma.","authors":"Sha Ma, Jieyun Xia, Miao Zhang, Wenyu Li, Meng Xiao, Yuqian Sha, Wenya Wang, Jianteng Zhou, Ying Wang, Kunming Qi, Chunling Fu, Zengtian Sun, Dian Zhou, Qian Sun, Tingting Qiu, Zhiling Yan, Feng Zhu, Wei Chen, Hai Cheng, Wei Sang, Jiang Cao, Depeng Li, Zhenyu Li, Mariateresa Fulciniti, Yao Yao, Kailin Xu, Mingshan Niu","doi":"10.1182/blood.2024026622","DOIUrl":"10.1182/blood.2024026622","url":null,"abstract":"Abstract: G protein-coupled receptor, class C, group 5, member D (GPRC5D) has emerged as a novel target for chimeric antigen receptor (CAR) T-cell therapy, demonstrating promising efficacy in multiple myeloma (MM). However, disease relapse is still common, and the mechanism of resistance remains poorly understood. In this study, we conducted whole-genome sequencing and whole-genome bisulfite sequencing on MM samples from 10 patients who relapsed after GPRC5D CAR T-cell therapy. Among these patients, 8 had GPRC5D loss, whereas 2 presented mixed expression (GPRC5D+/-). Genetic alterations were identified in 3 cases: one had a homozygous deletion in the GPRC5D gene, another had a biallelic loss in the regulatory regions of GPRC5D, and the third had homozygous deletions in both TNFRSF17 and GPRC5D after sequential anti-B-cell maturation antigen and anti-GPRC5D CAR T-cell therapies. No genetic changes were detected at GPRC5D locus in the remaining 7 cases. However, multiple hypermethylation sites were present in the transcriptional regulatory elements of the GPRC5D gene in 5 post-treatment MM samples. In MM cell lines, GPRC5D expression was inversely correlated with methylation levels in its regulatory regions. Furthermore, azacitidine treatment induced GPRC5D messenger RNA and protein expression in hypermethylated MM cell lines. Our findings highlight that biallelic genetic inactivation and hypermethylation-driven epigenetic silencing are key mechanisms contributing to GPRC5D loss and treatment resistance.","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"178-190"},"PeriodicalIF":21.0,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143639596","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