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A T-ALL order: a new risk classifier for T-ALL. T-ALL 订单:T-ALL 的新风险分类器。
IF 20.3 1区 医学 Q1 HEMATOLOGY Pub Date : 2024-10-10 DOI: 10.1182/blood.2024025623
Haley Newman,David T Teachey
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引用次数: 0
Optimizing drug combinations for T-PLL: restoring DNA damage and P53-mediated apoptotic responses. 优化治疗 T-PLL 的药物组合:恢复 DNA 损伤和 P53 介导的凋亡反应。
IF 21 1区 医学 Q1 HEMATOLOGY Pub Date : 2024-10-10 DOI: 10.1182/blood.2023022884
Jana von Jan, Sanna Timonen, Till Braun, Qu Jiang, Aleksandr Ianevski, Yayi Peng, Kathleen McConnell, Paola Sindaco, Tony Andreas Müller, Sabine Pützer, Hanna Klepzig, Dennis Jungherz, Annika Dechow, Linus Wahnschaffe, Anil K Giri, Matti Kankainen, Heikki Kuusanmäki, Heidi A Neubauer, Richard Moriggl, Paolo Mazzeo, Nicole Schmidt, Raphael Koch, Michael Hallek, Amel Chebel, David Armisen, Laurent Genestier, Emmanuel Bachy, Anjali Mishra, Alexandra Schrader, Tero Aittokallio, Satu Mustjoki, Marco Herling

Abstract: T-prolymphocytic leukemia (T-PLL) is a mature T-cell neoplasm associated with marked chemotherapy resistance and continued poor clinical outcomes. Current treatments, that is, the CD52-antibody alemtuzumab, offer transient responses, with relapses being almost inevitable without consolidating allogeneic transplantation. Recent more detailed concepts of T-PLL's pathobiology fostered the identification of actionable vulnerabilities: (1) altered epigenetics, (2) defective DNA damage responses, (3) aberrant cell-cycle regulation, and (4) deregulated prosurvival pathways, including T-cell receptor and JAK/STAT signaling. To further develop related preclinical therapeutic concepts, we studied inhibitors of histone deacetylases ([H]DACs), B-cell lymphoma 2 (BCL2), cyclin-dependent kinase (CDK), mouse double minute 2 (MDM2), and classical cytostatics, using (1) single-agent and combinatorial compound testing in 20 well-characterized and molecularly profiled primary T-PLL (validated by additional 42 cases) and (2) 2 independent murine models (syngeneic transplants and patient-derived xenografts). Overall, the most efficient/selective single agents and combinations (in vitro and in mice) included cladribine, romidepsin ([H]DAC), venetoclax (BCL2), and/or idasanutlin (MDM2). Cladribine sensitivity correlated with expression of its target RRM2. T-PLL cells revealed low overall apoptotic priming with heterogeneous dependencies on BCL2 proteins. In additional 38 T-cell leukemia/lymphoma lines, TP53 mutations were associated with resistance toward MDM2 inhibitors. P53 of T-PLL cells, predominantly in wild-type configuration, was amenable to MDM2 inhibition, which increased its MDM2-unbound fraction. This facilitated P53 activation and downstream signals (including enhanced accessibility of target-gene chromatin regions), in particular synergy with insults by cladribine. Our data emphasize the therapeutic potential of pharmacologic strategies to reinstate P53-mediated apoptotic responses. The identified efficacies and their synergies provide an informative background on compound and patient selection for trial designs in T-PLL.

T淋巴细胞白血病(T-PLL)是一种成熟的T细胞肿瘤,具有明显的化疗耐药性,临床疗效持续不佳。目前的治疗方法(如 CD52 抗体阿利珠单抗)只能提供短暂的反应,如果不进行巩固性异体移植,复发几乎不可避免。最近,人们对 T-PLL 的病理生物学有了更详细的概念,从而发现了可操作的薄弱环节:(i) 表观遗传学改变,(ii) DNA 损伤反应缺陷,(iii) 细胞周期调控失常,(iv) 促生存通路失调,包括 TCR 和 JAK/STAT 信号传导。为了进一步发展相关的临床前治疗概念,我们研究了(H)DACs、BCL2、CDK、MDM2和类细胞抑制剂的抑制剂,利用(a)单药和组合化合物测试了20个特征明确、分子特征清晰的原发性T-PLL(通过另外42个病例验证),以及(b)2个独立的小鼠模型(同种异体移植和患者来源异种移植)。总体而言,最有效/最有选择性的单一试剂和组合(体外和小鼠)包括 Cladribine、Romidepsin ((H)DAC)、Venetoclax (BCL2)和/或 Idasanutlin (MDM2)。克拉利宾的敏感性与其靶标 RRM2 的表达相关。T-PLL细胞的总体凋亡启动率较低,对BCL2蛋白的依赖性不同。在另外 38 个 T 细胞白血病/淋巴瘤系中,TP53 突变与对 MDM2 抑制剂的耐药性有关。T-PLL细胞中的P53主要是野生型结构,可被MDM2抑制,从而增加其与MDM2不结合的部分。这促进了 P53 的激活和下游信号(包括靶基因染色质再区域的可及性增强),尤其是与克拉德里滨的损伤协同作用。我们的数据强调了恢复 P53 介导的凋亡反应的药理策略的治疗潜力。已确定的疗效及其协同作用为 T-PLL 试验设计中的化合物和患者选择提供了信息背景。
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引用次数: 0
Use of HSC-targeted LNP to generate a mouse model of lethal α-thalassemia and treatment via lentiviral gene therapy. 利用造血干细胞靶向 LNP 生成致死性 α-地中海贫血小鼠模型并通过慢病毒基因疗法进行治疗。
IF 21 1区 医学 Q1 HEMATOLOGY Pub Date : 2024-10-10 DOI: 10.1182/blood.2023023349
Maxwell E Chappell, Laura Breda, Lucas Tricoli, Amaliris Guerra, Danuta Jarocha, Carlo Castruccio Castracani, Tyler E Papp, Naoto Tanaka, Nolan Hamilton, Michael P Triebwasser, Valentina Ghiaccio, Megan T Fedorky, Kandace L Gollomp, Veronica Bochenek, Aoife M Roche, John K Everett, Emma J Cook, Frederic D Bushman, Nattiya Teawtrakul, Stavros Glentis, Antonis Kattamis, Barbara L Mui, Ying K Tam, Drew Weissman, Osheiza Abdulmalik, Hamideh Parhiz, Stefano Rivella

Abstract: α-Thalassemia (AT) is one of the most commonly occurring inherited hematological diseases. However, few treatments are available, and allogeneic bone marrow transplantation is the only available therapeutic option for patients with severe AT. Research into AT has remained limited because of a lack of adult mouse models, with severe AT typically resulting in in utero lethality. By using a lipid nanoparticle (LNP) targeting the receptor CD117 and delivering a Cre messenger RNA (mRNACreLNPCD117), we were able to delete floxed α-globin genes at high efficiency in hematopoietic stem cells (HSC) ex vivo. These cells were then engrafted in the absence or presence of a novel α-globin-expressing lentiviral vector (ALS20αI). Myeloablated mice infused with mRNACreLNPCD117-treated HSC showed a complete knock out (KO) of α-globin genes. They showed a phenotype characterized by the synthesis of hemoglobin H (HbH; also known as β-tetramers or β4), aberrant erythropoiesis, and abnormal organ morphology, culminating in lethality ∼8 weeks after engraftment. Mice infused with mRNACreLNPCD117-treated HSC with at least 1 copy of ALS20αI survived long term with normalization of erythropoiesis, decreased production of HbH, and amelioration of the abnormal organ morphology. Furthermore, we tested ALS20αI in erythroid progenitors derived from α-globin-KO CD34+ cells and cells isolated from patients with both deletional and nondeletional HbH disease, demonstrating improvement in α-globin/β-globin mRNA ratio and reduction in the formation of HbH by high-performance liquid chromatography. Our results demonstrate the broad applicability of LNP for disease modeling, characterization of a novel mouse model of severe AT, and the efficacy of ALS20αI for treating AT.

 地中海贫血症(AT)是最常见的遗传性血液病之一。然而,目前可用的治疗方法很少,异基因骨髓移植(BMT)是重症地中海贫血患者唯一可用的治疗方法。由于缺乏成年小鼠模型,对AT的研究一直很有限,而严重的AT通常会导致胎死腹中。通过使用靶向 CD117 受体的脂质纳米颗粒(LNP)和递送 Cre mRNA(mRNACreLNPCD117),我们能够在体外造血干细胞(HSC)中高效地删除 -globin 基因。然后在没有或有新型α-球蛋白表达慢病毒载体(ALS20I)的情况下移植这些细胞。移植了经 mRNACreLNPCD117 处理的造血干细胞的小鼠表现出 -globin 基因的完全敲除。它们表现出的表型以血红蛋白 H 的合成(-tetramers, 或 HbH)、红细胞生成异常和器官形态异常为特征,最终在移植后约八周死亡。小鼠接受了经 mRNACreLNPCD117 处理且至少含有一个 ALS20I 拷贝的造血干细胞后,红细胞生成正常化、HbH 生成减少、器官形态异常改善,从而长期存活下来。此外,我们还在来源于 -globin-KO CD34+ 的红细胞祖细胞以及从缺失性和非缺失性 HbH 疾病患者分离的细胞中测试了 ALS20I,结果显示 -globin/-globin mRNA 比值有所改善,HPLC 检测显示 HbH 的形成有所减少。我们的研究结果证明了 LNP 在疾病建模方面的广泛适用性、新型严重 AT 小鼠模型的特征以及 ALS20I 治疗 AT 的疗效。
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引用次数: 0
Friedberg JW, Bordoni R, Patel-Donnelly D, et al. Brentuximab vedotin with dacarbazine or nivolumab as frontline cHL therapy for older patients ineligible for chemotherapy. Blood. 2024;143(9):786-795. Friedberg JW, Bordoni R, Patel-Donnelly D, et al. Brentuximab vedotin 与达卡巴嗪或 nivolumab 作为不符合化疗条件的老年 cHL 患者的前线疗法。Blood.2024;143(9):786-795.
IF 21 1区 医学 Q1 HEMATOLOGY Pub Date : 2024-10-10 DOI: 10.1182/blood.2024026833
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引用次数: 0
NGS-based stratification refines the risk stratification in T-ALL and identifies a very-high-risk subgroup of patients. 基于 NGS 的分层方法完善了 T-ALL 的风险分层,并确定了极高风险亚组患者。
IF 21 1区 医学 Q1 HEMATOLOGY Pub Date : 2024-10-10 DOI: 10.1182/blood.2023023754
Mathieu Simonin, Loïc Vasseur, Etienne Lengliné, Ludovic Lhermitte, Aurélie Cabannes-Hamy, Marie Balsat, Aline Schmidt, Marie-Emilie Dourthe, Aurore Touzart, Carlos Graux, Nathalie Grardel, Jean-Michel Cayuela, Isabelle Arnoux, Virginie Gandemer, Françoise Huguet, Stéphane Ducassou, Véronique Lhéritier, Yves Chalandon, Norbert Ifrah, Hervé Dombret, Elizabeth Macintyre, Arnaud Petit, Philippe Rousselot, Jérôme Lambert, André Baruchel, Nicolas Boissel, Vahid Asnafi

Abstract: We previously reported a better outcome in adult and pediatric T-cell acute lymphoblastic leukemia (T-ALL) harboring NOTCH1 and/or FBXW7 mutations without alterations of K-N-RAS and PTEN genes. Availability of high-throughput next-generation sequencing (NGS) strategies led us to refine the outcome prediction in T-ALL. Targeted whole-exome sequencing of 72 T-ALL-related oncogenes was performed in 198 adults with T-ALLs in first remission from the GRAALL-2003/2005 protocols and 242 pediatric patients with T-ALLs from the FRALLE2000T. This approach enabled the identification of, to our knowledge, the first NGS-based classifier in T-ALL, categorizing low-risk patients as those with N/F, PHF6, or EP300 mutations, excluding N-K-RAS, PI3K pathway (PTEN, PIK3CA, and PIK3R1), TP53, DNMT3A, IDH1/2, and IKZF1 alterations, with a 5-year cumulative incidence of relapse (CIR) estimated at 21%. Conversely, the remaining patients were classified as high risk, exhibiting a 5-year CIR estimated at 47%. We externally validated this stratification in the pediatric cohort. NGS-based classifier was highly prognostic independently of minimal residual disease (MRD) and white blood cell (WBC) counts, in both adult and pediatric cohorts. Integration of the NGS-based classifier into a comprehensive risk-stratification model, including WBC count at diagnosis and MRD at the end of induction, enabled the identification of an adverse-risk subgroup (25%) with a 5-year CIR estimated at 51%, and a favorable-risk group (32%) with a 5-year CIR estimated at 12%. NGS-based stratification combined with WBC and MRD sharpens the prognostic classification in T-ALL and identifies a new subgroup of patients who may benefit from innovative therapeutic approaches. The GRAALL-2003/2005 studies were registered at www.ClinicalTrials.gov as #NCT00222027 and #NCT00327678.

我们以前曾报道过,成人和儿童 T 细胞急性淋巴细胞白血病(T-ALL)如果携带 NOTCH1 和/或 FBXW7 基因突变,而 K-N-RAS 和 PTEN 基因没有改变,则会有更好的预后。高通量新一代测序策略(NGS)的出现使我们得以完善T-ALL的预后预测。我们对来自 GRAALL-2003/2005 方案(ClinicalTrial.gov,NCT00222027,NCT00327678)的 198 例首次缓解(CR1)的成人 T-ALL 和来自 FRALLE2000T 的 242 例儿童 T-ALL 进行了 72 个 T-ALL 相关癌基因的靶向全外显子组测序。通过这种方法确定了首个基于 NGS 的 T-ALL 分类器,将低风险患者分为 N/F、PHF6 或 EP300 突变的患者,排除 N-K-RAS、PI3K 通路(PTEN、PIK3CA 和 PIK3R1)、TP53、DNMT3A、IDH1/2 和 IKZF1 改变的患者,5 年累积复发率 (CIR) 估计为 21%。相反,其余患者被归类为高危患者,5 年累积复发率(CIR)估计为 47%。我们在儿科队列中对这一分层方法进行了外部验证。在成人和儿童队列中,基于 NGS 的分类器具有高度预后性,不受最小残留病(MRD)和白细胞计数(WBC)的影响。将基于 NGS 的分类器整合到综合风险分层模型(包括诊断时的白细胞计数和诱导结束时的 MRD)中,可以识别出一个不良风险亚组(25%)和一个良好风险组(32%),前者的 5 年 CIR 估计为 51%,后者的 5 年 CIR 估计为 12%。基于 NGS 的分层结合 WBC 和 MRD 使 T-ALL 的预后分类更加清晰,并确定了可能从创新治疗方法中获益的新患者亚群。
{"title":"NGS-based stratification refines the risk stratification in T-ALL and identifies a very-high-risk subgroup of patients.","authors":"Mathieu Simonin, Loïc Vasseur, Etienne Lengliné, Ludovic Lhermitte, Aurélie Cabannes-Hamy, Marie Balsat, Aline Schmidt, Marie-Emilie Dourthe, Aurore Touzart, Carlos Graux, Nathalie Grardel, Jean-Michel Cayuela, Isabelle Arnoux, Virginie Gandemer, Françoise Huguet, Stéphane Ducassou, Véronique Lhéritier, Yves Chalandon, Norbert Ifrah, Hervé Dombret, Elizabeth Macintyre, Arnaud Petit, Philippe Rousselot, Jérôme Lambert, André Baruchel, Nicolas Boissel, Vahid Asnafi","doi":"10.1182/blood.2023023754","DOIUrl":"10.1182/blood.2023023754","url":null,"abstract":"<p><strong>Abstract: </strong>We previously reported a better outcome in adult and pediatric T-cell acute lymphoblastic leukemia (T-ALL) harboring NOTCH1 and/or FBXW7 mutations without alterations of K-N-RAS and PTEN genes. Availability of high-throughput next-generation sequencing (NGS) strategies led us to refine the outcome prediction in T-ALL. Targeted whole-exome sequencing of 72 T-ALL-related oncogenes was performed in 198 adults with T-ALLs in first remission from the GRAALL-2003/2005 protocols and 242 pediatric patients with T-ALLs from the FRALLE2000T. This approach enabled the identification of, to our knowledge, the first NGS-based classifier in T-ALL, categorizing low-risk patients as those with N/F, PHF6, or EP300 mutations, excluding N-K-RAS, PI3K pathway (PTEN, PIK3CA, and PIK3R1), TP53, DNMT3A, IDH1/2, and IKZF1 alterations, with a 5-year cumulative incidence of relapse (CIR) estimated at 21%. Conversely, the remaining patients were classified as high risk, exhibiting a 5-year CIR estimated at 47%. We externally validated this stratification in the pediatric cohort. NGS-based classifier was highly prognostic independently of minimal residual disease (MRD) and white blood cell (WBC) counts, in both adult and pediatric cohorts. Integration of the NGS-based classifier into a comprehensive risk-stratification model, including WBC count at diagnosis and MRD at the end of induction, enabled the identification of an adverse-risk subgroup (25%) with a 5-year CIR estimated at 51%, and a favorable-risk group (32%) with a 5-year CIR estimated at 12%. NGS-based stratification combined with WBC and MRD sharpens the prognostic classification in T-ALL and identifies a new subgroup of patients who may benefit from innovative therapeutic approaches. The GRAALL-2003/2005 studies were registered at www.ClinicalTrials.gov as #NCT00222027 and #NCT00327678.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":null,"pages":null},"PeriodicalIF":21.0,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141287754","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
The intestinal microbiota and cellular therapy: implications for impact and mechanisms. 肠道微生物群与细胞疗法:影响与机制。
IF 21 1区 医学 Q1 HEMATOLOGY Pub Date : 2024-10-10 DOI: 10.1182/blood.2024024219
Jiayi Xie, Melody Smith

Abstract: The microbiota, comprising bacteria, fungi, and viruses residing within our bodies, functions as a key modulator in host health and states, including immune responses. Studies have linked microbiota and microbiota-derived metabolites to immune cell functions. In this review, we probe the complex relationship between the human microbiota and clinical outcomes of cellular therapies that leverage immune cells to fight various cancers. With a particular emphasis on hematopoietic cell transplantation and chimeric antigen receptor T-cell therapy, we explore the potential mechanisms underpinning this interaction. We also highlight the interventional applications of the microbiota in cellular therapy while outlining future research directions in the field.

微生物群由居住在人体内的细菌、真菌和病毒组成,是调节宿主健康和状态(包括免疫反应)的关键因素。研究已将微生物群和微生物群衍生代谢物与免疫细胞功能联系起来。在这篇综述中,我们将探讨人体微生物群与利用免疫细胞对抗各种癌症的细胞疗法的临床结果之间的复杂关系。我们特别强调了造血细胞移植和嵌合抗原受体 T 细胞疗法,探讨了这种相互作用的潜在机制。我们还强调了细胞疗法中微生物群的干预应用,同时概述了该领域未来的研究方向。
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引用次数: 0
Genetic alteration of class I HLA in cutaneous T-cell lymphoma. 皮肤 T 细胞淋巴瘤中 I 类 HLA 的基因改变。
IF 21 1区 医学 Q1 HEMATOLOGY Pub Date : 2024-10-10 DOI: 10.1182/blood.2024024817
Alexa C Kwang, George E Duran, Sebastian Fernandez-Pol, Safa Najidh, Shufeng Li, Armando N Bastidas Torres, Erica B Wang, Melba Herrera, Tarek I Bandali, David M Kurtz, Youn H Kim, Michael S Khodadoust

Abnormalities involving class I HLA are frequent in many lymphoma subtypes but have not yet been extensively studied in cutaneous T-cell lymphomas (CTCL). We characterized the occurrence of class I HLA abnormalities in 65 patients with advanced mycosis fungoides (MF) or Sézary syndrome (SS). Targeted DNA sequencing including coverage of HLA loci revealed at least one HLA abnormality in 26/65 patients (40%). Twelve unique somatic HLA mutations were identified across nine patients, and loss of heterozygosity or biallelic loss of HLA was found to affect 24 patients. Although specific HLA alleles were commonly disrupted, these events did not associate with decreased total class I HLA expression. Genetic events preferentially disrupted HLA alleles capable of presentation of greater numbers of putative neoantigens. HLA abnormalities co-occurred with other genetic immune evasion events and were associated with worse progression-free survival. Single-cell analyses demonstrated HLA abnormalities were frequently subclonal. Through analysis of serial samples, we observed disrupting class I HLA events change dynamically over the disease course. The dynamics of HLA disruption are highlighted in a patient receiving pembrolizumab, where resistance to pembrolizumab was associated with elimination of an HLA mutation. Overall, our findings show that genomic class I HLA abnormalities are common in advanced CTCL and may be an important consideration in understanding the effects of immunotherapy in CTCL.

I 类 HLA 异常在许多淋巴瘤亚型中都很常见,但在皮肤 T 细胞淋巴瘤 (CTCL) 中尚未得到广泛研究。我们对 65 例晚期真菌病(MF)或塞扎里综合征(SS)患者的 I 类 HLA 异常进行了鉴定。包括HLA基因位点覆盖在内的靶向DNA测序发现,26/65例患者(40%)中至少有一种HLA异常。9名患者中发现了12种独特的体细胞HLA突变,24名患者中发现了HLA杂合性缺失或双倍性缺失。虽然特定的HLA等位基因通常会被破坏,但这些事件与I类HLA总表达的减少无关。基因事件更倾向于破坏能够表达更多假定新抗原的HLA等位基因。HLA异常与其他遗传性免疫逃避事件同时发生,并与无进展生存期缩短有关。单细胞分析表明,HLA异常常常是亚克隆性的。通过对序列样本的分析,我们观察到干扰I类HLA的事件在病程中发生动态变化。HLA破坏的动态变化在一名接受pembrolizumab治疗的患者身上得到了突显,该患者对pembrolizumab的耐药与HLA突变的消除有关。总之,我们的研究结果表明,基因组 I 类 HLA 异常在晚期 CTCL 中很常见,可能是了解 CTCL 免疫疗法效果的一个重要考虑因素。
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引用次数: 0
Constitutive STAT5 activation in precursor B-cell acute lymphoblastic leukemia with P2RY8::CRLF2 fusion. P2RY8::CRLF2融合的前体B细胞急性淋巴细胞白血病中STAT5的持续激活。
IF 21 1区 医学 Q1 HEMATOLOGY Pub Date : 2024-10-10 DOI: 10.1182/blood.2024025958
Roxanne Nieder, Weijie Li
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引用次数: 0
Targeting therapeutic vulnerabilities in T-PLL. 针对 T-PLL 的治疗弱点。
IF 21 1区 医学 Q1 HEMATOLOGY Pub Date : 2024-10-10 DOI: 10.1182/blood.2024025596
Marwan Kwok, Tatjana Stankovic
{"title":"Targeting therapeutic vulnerabilities in T-PLL.","authors":"Marwan Kwok, Tatjana Stankovic","doi":"10.1182/blood.2024025596","DOIUrl":"10.1182/blood.2024025596","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":null,"pages":null},"PeriodicalIF":21.0,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142406071","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
GSDME-mediated Pyroptosis Contributes to Chemotherapy-induced Platelet Hyperactivity and Thrombotic Potential. GSDME 介导的热蛋白沉积有助于化疗引起的血小板过度活跃和血栓形成。
IF 21 1区 医学 Q1 HEMATOLOGY Pub Date : 2024-10-08 DOI: 10.1182/blood.2023023179
Ruyi Xue, Min Li, Ge Zhang, Wei Zhang, Liping Han, Tao Bo, Haoxuan Zhong, Dingjin Yao, Yiran Deng, She Chen, Si Zhang

Thrombotic complications due to platelet hyperreactivity are a major cause of death in patients undergoing chemotherapy. However, the underlying mechanisms are not fully understood. Herein, using human and GSDME-/- mouse platelets, we showed that GSDME is functionally expressed in anucleate platelets and GSDME-mediated pyroptosis, a newly identified form of cell death in mammalian nucleated cells, contributes to platelet hyperactivity in cisplatin-based chemotherapy. Cisplatin or etoposide activates caspase-3 to cleave GSDME, thereby releasing the N-terminal fragment of GSDME (GSDME-N) toward the platelet plasma membrane, subsequently forming membrane pores and facilitating platelet granule release. This eventually promotes platelet hyperactivity and thrombotic potential. We identified flotillin-2, a scaffold protein, as a GSDME-N interactor that recruits GSDME-N to the platelet membrane. loss of GSDME protects mice from cisplatin-induced platelet hyperactivity. Our results provide evidence that targeting GSDME-mediated pyroptosis could reduce thrombotic potential in chemotherapy.

血小板高反应性导致的血栓并发症是化疗患者死亡的主要原因。然而,其潜在机制尚未完全明了。在此,我们利用人体血小板和GSDME-/-小鼠血小板研究发现,GSDME在无核血小板中有功能表达,GSDME介导的热凋亡(哺乳动物有核细胞中一种新发现的细胞死亡形式)是顺铂化疗中血小板过度活跃的原因。顺铂或依托泊苷激活 Caspase-3 裂解 GSDME,从而向血小板质膜释放 GSDME 的 N 端片段(GSDME-N),随后形成膜孔,促进血小板颗粒释放。这最终会促进血小板的过度活跃和血栓形成的可能性。我们发现支架蛋白 flotillin-2 是 GSDME-N 的相互作用因子,它能将 GSDME-N 募集到血小板膜上。我们的研究结果为靶向 GSDME 介导的热凋亡提供了证据,可以降低化疗中血栓形成的可能性。
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引用次数: 0
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