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The high-grade B-cell lymphomas: Double hit and more. 高级别 B 细胞淋巴瘤:双击和更多
IF 20.3 1区 医学 Q1 HEMATOLOGY Pub Date : 2024-10-20 DOI: 10.1182/blood.2023020780
Andrew J Davies
Both the 2022 WHO HAEM5 and the International Consensus Classification of lymphoma have refined the way we now approach high-grade B-cell lymphoma (HGBL) with MYC and BCL2 and/or BCL6 rearrangements moving the previous generation of classification a step forward. The unifying biology of MYC/BCL2 tumours has been clearer and their inferior prognosis confirmed compared to those with morphological similarities but lacking the classifying cytogenetic abnormalities. FISH testing has largely become population based and we have learnt much from this. We can readily define molecular categories and apply these widely to clinical practice. Uncertainty has however been shed upon the place of double MYC/BCL6 translocations in defining a common disease group. We have enhanced knowledge of outcomes and the role of therapy intensification to overcome chemotherapy resistance. For those patients failed by initial induction chemotherapy, immunotherapy approaches, including CAR-T therapies, are improving outcomes. Novel inhibitors, targeting dysregulated oncogenic proteins are being explored at pace. The rare, but difficult, diagnostic classification HGBL (NOS) remains a diagnosis of exclusion with limited data on an optimal clinical approach. The days of talking loosely of double and triple hit lymphoma are numbered as this review synergises the current data on biology, prognosis, and therapies in HGBL.
2022 年世界卫生组织 HAEM5 和淋巴瘤国际共识分类法都完善了我们现在处理 MYC 和 BCL2 和/或 BCL6 重排的高级别 B 细胞淋巴瘤 (HGBL) 的方法,使上一代分类法向前迈进了一步。MYC/BCL2肿瘤的统一生物学特性更加明确,与形态学相似但缺乏分类细胞遗传学异常的肿瘤相比,它们的预后较差。FISH 检测在很大程度上以人群为基础,我们也从中学习到了很多。我们可以很容易地定义分子分类,并将其广泛应用于临床实践。然而,双 MYC/BCL6 易位在定义常见疾病组别中的地位还存在不确定性。我们对疗效和强化治疗在克服化疗耐药性方面的作用有了更深入的了解。对于初始诱导化疗失败的患者,包括 CAR-T 疗法在内的免疫疗法正在改善其预后。针对调控失调的致癌蛋白的新型抑制剂也在不断探索之中。HGBL (NOS)这种罕见但难以诊断的分类仍然是一种排除性诊断,关于最佳临床方法的数据十分有限。本综述汇集了目前有关 HGBL 的生物学、预后和疗法的数据,因此,笼统地谈论双重和三重打击淋巴瘤的时代已经一去不复返了。
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引用次数: 0
The high-grade B-cell lymphomas: Double hit and more. 高级别 B 细胞淋巴瘤:双击及更多
IF 21 1区 医学 Q1 HEMATOLOGY Pub Date : 2024-10-20 DOI: 10.1182/blood.2023020780
Andrew J Davies

Both the 2022 WHO HAEM5 and the International Consensus Classification of lymphoma have refined the way we now approach high-grade B-cell lymphoma (HGBL) with MYC and BCL2 and/or BCL6 rearrangements moving the previous generation of classification a step forward. The unifying biology of MYC/BCL2 tumours has been clearer and their inferior prognosis confirmed compared to those with morphological similarities but lacking the classifying cytogenetic abnormalities. FISH testing has largely become population based and we have learnt much from this. We can readily define molecular categories and apply these widely to clinical practice. Uncertainty has however been shed upon the place of double MYC/BCL6 translocations in defining a common disease group. We have enhanced knowledge of outcomes and the role of therapy intensification to overcome chemotherapy resistance. For those patients failed by initial induction chemotherapy, immunotherapy approaches, including CAR-T therapies, are improving outcomes. Novel inhibitors, targeting dysregulated oncogenic proteins are being explored at pace. The rare, but difficult, diagnostic classification HGBL (NOS) remains a diagnosis of exclusion with limited data on an optimal clinical approach. The days of talking loosely of double and triple hit lymphoma are numbered as this review synergises the current data on biology, prognosis, and therapies in HGBL.

2022 年世界卫生组织 HAEM5 和淋巴瘤国际共识分类法都完善了我们现在处理 MYC 和 BCL2 和/或 BCL6 重排的高级别 B 细胞淋巴瘤 (HGBL) 的方法,使上一代分类法向前迈进了一步。MYC/BCL2肿瘤的统一生物学特性更加明确,与形态学相似但缺乏分类细胞遗传学异常的肿瘤相比,它们的预后较差。FISH 检测在很大程度上以人群为基础,我们也从中学习到了很多。我们可以很容易地定义分子分类,并将其广泛应用于临床实践。然而,双 MYC/BCL6 易位在定义常见疾病组别方面的地位还存在不确定性。我们对疗效和强化治疗在克服化疗耐药性方面的作用有了更深入的了解。对于初始诱导化疗失败的患者,包括 CAR-T 疗法在内的免疫疗法正在改善其预后。针对调控失调的致癌蛋白的新型抑制剂也在不断探索之中。HGBL (NOS)这种罕见但难以诊断的分类仍然是一种排除性诊断,关于最佳临床方法的数据十分有限。本综述汇集了当前有关 HGBL 的生物学、预后和疗法的数据,因此,笼统地谈论双重和三重打击淋巴瘤的时代已经一去不复返了。
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引用次数: 0
Platelets burst your bubble. 血小板戳破你的泡沫
IF 21 1区 医学 Q1 HEMATOLOGY Pub Date : 2024-10-17 DOI: 10.1182/blood.2024025270
Robert Flaumenhaft
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引用次数: 0
Inhibition of RHOA activity preserves the survival and hemostasis function of long-term cold-stored platelets. 抑制 RHOA 活性可保持长期冷藏血小板的存活和止血功能。
IF 21 1区 医学 Q1 HEMATOLOGY Pub Date : 2024-10-17 DOI: 10.1182/blood.2023021453
Shailaja Hegde, Huzoor Akbar, Ashley M Wellendorf, Shawnagay Nestheide, James F Johnson, Xueheng Zhao, Kenneth D Setchell, Yi Zheng, Jose A Cancelas

Abstract: Patients with thrombocytopenia require platelet transfusion to prevent and stop hemorrhage. Cold storage of platelets results in complex molecular lesions, including changes in membrane microdomains that are recognized by host macrophages and hepatocyte counter-receptors, resulting in phagocytosis and clearance upon transfusion. For this reason, platelets are stored at room temperature, a method that confers increased risk of bacterial contamination. By applying signaling analysis and genetic and pharmacological approaches, we identified that cold-induced activation of RAS homolog family, member A (RHOA) GTPase causes the major hallmarks of platelet cold storage lesions. RHOA deficiency renders murine platelets insensitive to cold storage-induced damage, and pharmacological inhibition by a RHOA activation inhibitor, R-G04, can prevent the cold storage-induced lesions. RHOA inhibition prevents myosin activation and clathrin-independent formation and internalization of lipid rafts enriched in active glycosyltransferases as well as abnormal distribution of GPIbα. RHOA inhibition further prevents the metabolic reprogramming of cold storage-induced lesions and allows the maintenance of glycolytic flux and mitochondria-dependent respiration. Importantly, human platelets transfused in mice after cold storage, in the presence of R-G04 or its more potent enantiomer S-G04, can circulate in vivo at similar levels as room temperature-stored platelets while retaining their hemostatic activity in vivo, as assessed by bleeding time correction in aspirin-treated mice. Our studies provide a mechanism-based translational approach to prevent cold storage-induced damage, which is useful for human platelet transfusion in patients with thrombocytopenia.

血小板减少症患者需要输注血小板来预防和止血。血小板冷藏会导致复杂的分子病变,包括膜微域的变化,这些变化会被宿主巨噬细胞和肝细胞反受体识别,从而导致吞噬和输血时的清除。因此,血小板被储存在室温下,这种方法增加了细菌污染的风险。通过信号分析以及基因和药理学方法,我们发现冷诱导的 RHOA GTPase 激活是血小板冷藏病变主要特征的成因。RHOA 缺乏会使小鼠血小板对冷藏诱导的损伤不敏感,而 RHOA 激活抑制剂 R-G04 的药理抑制作用可防止冷藏诱导的病变。RHOA 抑制剂可防止肌球蛋白活化和不依赖于凝集素的富含活性糖基转移酶的脂质筏的形成和内化,以及 GpIb 的异常分布。抑制 RHOA 可进一步防止冷诱导的贮存病变的代谢重编程,并使糖酵解通量和线粒体依赖性呼吸得以维持。重要的是,在 R-G04 或其更强效的对映体 S-G04 的作用下,冷藏后输给小鼠的人类血小板在体内的循环水平与室温储存的血小板相似,同时还能保留其体内止血活性,这是由阿司匹林处理的小鼠的出血时间校正所评估的。我们的研究为防止低温储存引起的损伤提供了一种新的机制,可用于血小板减少症患者的人体血小板输注。
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引用次数: 0
Influence of TP53 gene mutations and their allelic status in myelodysplastic syndromes with isolated 5q deletion. TP53基因突变及其等位基因状态对孤立5q缺失骨髓增生异常综合征的影响
IF 21 1区 医学 Q1 HEMATOLOGY Pub Date : 2024-10-17 DOI: 10.1182/blood.2024023840
Maria Julia Montoro, Laura Palomo, Claudia Haferlach, Pamela Acha, Onyee Chan, Víctor Navarro, Yasuo Kubota, Felicitas Isabel Schulz, Manja Meggendorfer, Robert Briski, Najla Al Ali, Blanca Xicoy, Félix López-Cadenas, Francesc Bosch, Teresa González, Lea Naomi Eder, Andrés Jerez, Yu-Hung Wang, Alessia Campagna, Valeria Santini, Teresa Bernal Del Castillo, Esperanza Such, Hwei-Fang Tien, Nicolás Diaz Varela, Uwe Platzbecker, Detlef Haase, María Díez-Campelo, Matteo Della Porta, Guillermo Garcia-Manero, Daniel H Wiseman, Ulrich Germing, Jaroslaw P Maciejewski, Rami S Komrokji, Francesc Sole, Torsten Haferlach, David Valcárcel

Abstract: Mutations in the TP53 gene, particularly multihit alterations, have been associated with unfavorable clinical features and prognosis in patients diagnosed with myelodysplastic syndrome (MDS). Despite this, the role of TP53 gene aberrations in MDS with isolated deletion of chromosome 5 [MDS-del(5q)] remains unclear. This study aimed to assess the impact of TP53 gene mutations and their allelic state in patients with MDS-del(5q). To that end, a comprehensive analysis of TP53 abnormalities, examining both TP53 mutations and allelic imbalances, in 682 patients diagnosed with MDS-del(5q) was conducted. Twenty-four percent of TP53-mutated patients exhibited multihit alterations, whereas the remaining patients displayed monoallelic mutations. TP53-multihit alterations were predictive of an increased risk of leukemic transformation. The impact of monoallelic alterations was dependent on the variant allele frequency (VAF); patients with TP53-monoallelic mutations and VAF <20% exhibited behavior similar to TP53 wild type, and those with TP53-monoallelic mutations and VAF ≥20% presented outcomes equivalent to TP53-multihit patients. This study underscores the importance of considering TP53 allelic state and VAF in the risk stratification and treatment decision-making process for patients with MDS-del(5q).

TP53基因突变,尤其是多位基因改变,与骨髓增生异常综合征(MDS)患者的不良临床特征和预后有关。尽管如此,TP53基因畸变在伴有5号染色体孤立缺失的MDS[MDS-del(5q)]中的作用仍不明确。本研究旨在评估TP53基因突变及其等位基因状态对MDS-del(5q)患者的影响。为此,研究人员对682名确诊为MDS-del(5q)患者的TP53异常情况进行了全面分析,包括TP53基因突变和等位基因失衡。24%的TP53突变患者表现出多基因突变,而其余患者则表现出单等位基因突变。TP53多位变异可预测白血病转化风险的增加。单等位基因改变的影响取决于变异等位基因频率(VAF);TP53单等位基因突变患者的VAF
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引用次数: 0
Directionality of HLA-DP permissive mismatches improves risk prediction in HCT for acute leukemia and MDS. HLA-DP 允许性错配的方向性提高了急性白血病和 MDS HCT 的风险预测能力。
IF 21 1区 医学 Q1 HEMATOLOGY Pub Date : 2024-10-17 DOI: 10.1182/blood.2024024351
Esteban Arrieta-Bolaños, Lars L J van der Burg, Tobias Gedde-Dahl, Marie Robin, Urpu Salmenniemi, Nicolaus Kröger, Ibrahim Yakoub-Agha, Anne Huynh, Charles Crawley, Eric Deconinck, Claude Eric Bulabois, Edouard Forcade, Eleni Tholouli, Joost G K van der Hem, Peter van Balen, Jorinde D Hoogenboom, Liesbeth C de Wreede, Florent Malard, Annalisa Ruggeri, Katharina Fleischhauer

Abstract: HLA-DP permissive mismatches can be assigned a direction according to their immunopeptidome divergence across core and noncore subsets. Noncore permissive graft-versus-host mismatches show significantly reduced risks of relapse without increased nonrelapse mortality compared with allele-matched pairs.

HLA-DP允许的错配可根据其在核心和非核心亚群中的免疫肽组分歧来确定方向。非核心允许的 GvH mM 显示复发风险显著降低(HR 0.77 [0.63-0.93]; p
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引用次数: 0
Long-noncoding vulnerabilities in MM. MM 中的长非编码漏洞。
IF 21 1区 医学 Q1 HEMATOLOGY Pub Date : 2024-10-17 DOI: 10.1182/blood.2024026358
Manuel Kaulich
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引用次数: 0
An unbiased lncRNA dropout CRISPR-Cas9 screen reveals RP11-350G8.5 as a novel therapeutic target for multiple myeloma. 无偏见的 lncRNAs dropout CRISPR-Cas9 筛选发现 RP11-350G8.5 是治疗多发性骨髓瘤的新靶点。
IF 21 1区 医学 Q1 HEMATOLOGY Pub Date : 2024-10-17 DOI: 10.1182/blood.2023021991
Katia Grillone, Serena Ascrizzi, Paolo Cremaschi, Jussara Amato, Nicoletta Polerà, Ottavio Croci, Roberta Rocca, Caterina Riillo, Francesco Conforti, Raffaele Graziano, Diego Brancaccio, Daniele Caracciolo, Stefano Alcaro, Bruno Pagano, Antonio Randazzo, Pierosandro Tagliaferri, Francesco Iorio, Pierfrancesco Tassone

Abstract: Multiple myeloma (MM) is an incurable malignancy characterized by altered expression of coding and noncoding genes promoting tumor growth and drug resistance. Although the crucial role of long noncoding RNAs (lncRNAs) in MM is clearly established, the function of the noncoding RNAome, which might allow the design of novel therapeutics, is largely unknown. We performed an unbiased CRISPR-Cas9 loss-of-function screen of 671 lncRNAs in MM cells and their bortezomib (BZB)-resistant derivative. To rank functionally and clinically relevant candidates, we designed and used a bioinformatic prioritization pipeline combining functional data from cellular screens with prognostic and transcriptional data from patients with MM. With this approach, we unveiled and prioritized 8 onco-lncRNAs essential for MM cell fitness, associated with high expression and poor prognosis in patients with MM. The previously uncharacterized RP11-350G8.5 emerged as the most promising target, irrespective of BZB resistance. We (1) demonstrated the anti-tumoral effect obtained by RP11-350G8.5 inhibition in vitro and in vivo; (2) highlighted a modulation of the unfolded protein response and the induction of immunogenic cell death triggered by the RP11-350G8.5 knockout, via RNA sequencing and molecular studies; (3) characterized its cytoplasmic homing through RNA fluorescence in situ hybridization; and (4) predicted its 2-dimensional structure and identified 2 G-quadruplex and 3 hairpin-forming regions by biophysical assays, including thioflavin T, 1H nuclear magnetic resonance, and circular dichroism, to pave the way to the development of novel targeted therapeutics. Overall, we provided innovative insights about unexplored lncRNAs in MM and identified RP11-350G8.5 as an oncogenic target for treatment-naïve and BZB-resistant patients with MM.

多发性骨髓瘤(MM)是一种无法治愈的恶性肿瘤,其特点是编码基因和非编码基因的表达发生了改变,从而促进了肿瘤的生长和耐药性的产生。尽管长非编码 RNA(lncRNA)在多发性骨髓瘤中的关键作用已得到明确证实,但人们对非编码 RNA 组的功能却知之甚少,而这可能有助于设计新型疗法。我们在MM细胞及其硼替佐米(BZB)抗性衍生物中对671个lncRNA进行了无偏见的CRISPR-Cas9功能缺失筛选。为了对功能和临床相关的候选基因进行排序,我们设计并使用了生物信息学优先排序管道,将细胞筛选的功能数据与 MM 患者的预后和转录数据相结合。通过这种方法,我们揭示并优先选择了 8 个对 MM 细胞健康至关重要的 onco-lncRNA,它们与 MM 患者的高表达和不良预后有关。之前未表征的 RP11-350G8.5 成为最有希望的靶点,与 BZB 抗性无关。我们 i) 证实了 RP11-350G8.5 抑制剂在体外和体内的抗肿瘤效果;ii) 强调了 RP11-350G8.5 基因敲除对未折叠蛋白反应的调节作用以及诱导免疫原性细胞死亡的作用。ii)通过 RNA 序列分析和分子研究,强调了 RP11-350G8.5 基因敲除对未折叠蛋白反应的调节作用和诱导免疫性细胞死亡的作用;iii)通过 RNA-FISH 分析了其细胞质归宿的特征;iv)通过生物物理检测,包括硫黄素 T、1H-NMR 和环二色性,预测了其二维结构并确定了 2 个 G 型四联体和 3 个发夹形成区,为开发新型靶向疗法铺平了道路。总之,我们提供了有关 MM 中未探索的 lncRNA 的创新见解,并发现 RP11-350G8.5 是治疗无效和对 BZB 耐药的 MM 患者的致癌靶点。
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引用次数: 0
Impact of TP53 in MDS with isolated del(5q). TP53 对伴有孤立 del(5q) 的 MDS 的影响。
IF 20.3 1区 医学 Q1 HEMATOLOGY Pub Date : 2024-10-17 DOI: 10.1182/blood.2024026010
Lionel Adès
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引用次数: 0
Soluble glycoprotein VI predicts abdominal aortic aneurysm growth rate and is a novel therapeutic target. 可溶性糖蛋白 VI 预测腹主动脉瘤的生长速度并成为新的治疗靶点
IF 21 1区 医学 Q1 HEMATOLOGY Pub Date : 2024-10-17 DOI: 10.1182/blood.2023021655
Tyler W Benson, Mindy M Pike, Anthony Spuzzillo, Sarah M Hicks, Sidra Ali, Michael Pham, Doran S Mix, Seth I Brunner, Caris Wadding-Lee, Kelsey A Conrad, Hannah M Russell, Courtney Jennings, Taylor M Coughlin, Anu Aggarwal, Sean Lyden, Kevin Mani, Martin Björck, Anders Wanhainen, Rohan Bhandari, Loren Lipworth-Elliot, Cassianne Robinson-Cohen, Francis J Caputo, Sharon Shim, Odayme Quesada, Benjamin Tourdot, Todd L Edwards, Michael Tranter, Elizabeth E Gardiner, Nigel Mackman, Scott J Cameron, A Phillip Owens

Abstract: A common feature in patients with abdominal aortic aneurysms (AAAs) is the formation of a nonocclusive intraluminal thrombus (ILT) in regions of aortic dilation. Platelets are known to maintain hemostasis and propagate thrombosis through several redundant activation mechanisms, yet the role of platelet activation in the pathogenesis of AAA-associated ILT is still poorly understood. Thus, we sought to investigate how platelet activation affects the pathogenesis of AAA. Using RNA sequencing, we identified that the platelet-associated transcripts are significantly enriched in the ILT compared with the adjacent aneurysm wall and healthy control aortas. We found that the platelet-specific receptor glycoprotein VI (GPVI) is among the top enriched genes in AAA ILT and is increased on the platelet surface of patients with AAAs. Examination of a specific indicator of platelet activity, soluble GPVI (sGPVI), in 2 independent cohorts of patients with AAAs is highly predictive of an AAA diagnosis and associates more strongly with aneurysm growth rate than D-dimer in humans. Finally, intervention with the anti-GPVI antibody (JAQ1) in mice with established aneurysms blunted the progression of AAA in 2 independent mouse models. In conclusion, we show that the levels of sGPVI in humans can predict a diagnosis of AAA and AAA growth rate, which may be critical in the identification of high-risk patients. We also identify GPVI as a novel platelet-specific AAA therapeutic target, with minimal risk of adverse bleeding complications, for which none currently exists.

腹主动脉瘤(AAA)患者的一个共同特征是在主动脉扩张区域形成非闭塞性腔内血栓(ILT)。众所周知,血小板通过几种多余的活化机制维持止血和传播血栓,但血小板活化在与 AAA 相关的 ILT 发病机制中的作用仍鲜为人知。因此,我们试图研究血小板活化如何影响 AAA 的发病机制。通过 RNA 测序,我们发现与邻近动脉瘤壁和健康对照主动脉相比,血小板相关转录本在 ILT 中明显富集。我们发现血小板特异性受体糖蛋白 VI (GPVI) 是 AAA ILT 中富集最多的基因之一,而且在 AAA 患者的血小板表面也有所增加。在两个独立的 AAA 患者队列中对血小板活性的特定指标--可溶性 GPVI(sGPVI)进行检测,发现它对 AAA 诊断具有很高的预测性,与人类的 D-二聚体相比,它与动脉瘤生长速度的关联性更强。最后,在两个独立的小鼠模型中,用抗 GPVI 抗体 (JAQ1) 对已形成动脉瘤的小鼠进行干预,可减缓 AAA 的发展。总之,我们的研究表明,人体内的 sGPVI 水平可以预测 AAA 的诊断和 AAA 的生长速度,这可能是识别高危患者的关键。我们还发现 GPVI 是一种新型血小板特异性 AAA 治疗靶点,其出血并发症的风险极低,而目前尚无此类靶点。
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引用次数: 0
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