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Endothelial inflammation: how many bad apples? 内皮炎症:有多少坏苹果?
IF 21 1区 医学 Q1 HEMATOLOGY Pub Date : 2024-11-07 DOI: 10.1182/blood.2024026451
Michael J Simmonds
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引用次数: 0
Are D+ units safe for D+ patients with anti-D? D+ 单位对抗 D 患者安全吗?
IF 21 1区 医学 Q1 HEMATOLOGY Pub Date : 2024-11-07 DOI: 10.1182/blood.2024026567
Nancy Robitaille, Gabriel André Leiva-Torres
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引用次数: 0
A simple score for clonal cytopenias. 克隆性细胞减少症的简单评分。
IF 21 1区 医学 Q1 HEMATOLOGY Pub Date : 2024-11-07 DOI: 10.1182/blood.2024026076
Torsten Haferlach
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引用次数: 0
Broken brakes: PRC loss foils menin inhibition. 刹车失灵:PRC 的损失挫败了 menin 的抑制作用。
IF 21 1区 医学 Q1 HEMATOLOGY Pub Date : 2024-11-07 DOI: 10.1182/blood.2024026297
Nahal Azimi, Aniruddha J Deshpande
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引用次数: 0
The promise of allosteric kinase inhibition. 异位激酶抑制剂的前景。
IF 21 1区 医学 Q1 HEMATOLOGY Pub Date : 2024-11-07 DOI: 10.1182/blood.2024026052
Neil P Shah
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引用次数: 0
Perspectives on drug development in chronic myelomonocytic leukemia: changing the paradigm. 慢性粒细胞白血病药物开发的前景:改变范式。
IF 21 1区 医学 Q1 HEMATOLOGY Pub Date : 2024-11-07 DOI: 10.1182/blood.2024025648
Anthony M Hunter, Mrinal M Patnaik, Raphael Itzykson, Ruben Mesa, Chatchada Karanes, Yanxia Li, R Angelo de Claro, Kelly J Norsworthy, Marc Theoret, Elizabeth Pulte, Eric Padron

Abstract: Drug development for chronic myelomonocytic leukemia (CMML) has failed to parallel the recent success observed in related myeloid neoplasms. To address these shortcomings, the US Food and Drug Administration (FDA) held a "Mini-symposium on CMML: Current State of the Art and Trial Design" in September 2023. This symposium brought together a panel of key FDA regulators and academic experts in CMML drug development to discuss challenges and provide perspectives on future drug development for this disease. The panel explored unique challenges that underlie the lack of therapeutic advances in CMML to date and discussed relevant topics such as clinical trial design, study end points, and key regulatory considerations. This article summarizes the key points of discussion from this symposium to facilitate advancements in the field.

摘要:慢性粒细胞白血病(CMML)的药物开发未能与最近在相关髓系肿瘤中观察到的成功相提并论。针对这些不足,美国食品药品管理局(FDA)于 20 年 9 月召开了 "慢性粒细胞白血病小型研讨会":当前技术水平和试验设计 "小型研讨会。此次研讨会汇集了 FDA 主要监管人员和 CMML 药物开发方面的学术专家,共同讨论了该疾病面临的挑战,并对该疾病未来的药物开发提出了看法。专家小组探讨了迄今为止 CMML 治疗缺乏进展所面临的独特挑战,并讨论了临床试验设计、研究终点和主要监管考虑因素等相关主题。本文总结了本次研讨会的讨论要点,以促进该领域的进步。
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引用次数: 0
NG2 is a target gene of MLL-AF4 and underlies glucocorticoid resistance in MLLr B-ALL by regulating NR3C1 expression. NG2是MLL-AF4的一个靶基因,通过调节NR3C1的表达成为MLL-r B-ALL耐糖皮质激素的基础。
IF 21 1区 医学 Q1 HEMATOLOGY Pub Date : 2024-11-07 DOI: 10.1182/blood.2023022050
Belén Lopez-Millan, Alba Rubio-Gayarre, Meritxell Vinyoles, Juan L Trincado, Mario F Fraga, Narcís Fernandez-Fuentes, Mercedes Guerrero-Murillo, Alba Martinez, Talia Velasco-Hernandez, Aïda Falgàs, Carla Panisello, Gemma Valcarcel, José Luis Sardina, Paula López-Martí, Biola M Javierre, Beatriz Del Valle-Pérez, Antonio García de Herreros, Franco Locatelli, Rob Pieters, Michela Bardini, Giovanni Cazzaniga, Juan Carlos Rodríguez-Manzaneque, Thomas Hanewald, Rolf Marschalek, Thomas A Milne, Ronald W Stam, Juan Ramón Tejedor, Pablo Menendez, Clara Bueno

Abstract: B-cell acute lymphoblastic leukemia (B-ALL) is the most common pediatric cancer, with long-term overall survival rates of ∼85%. However, B-ALL harboring rearrangements of the MLL gene (also known as KMT2A), referred to as MLLr B-ALL, is common in infants and is associated with poor 5-year survival, relapses, and refractoriness to glucocorticoids (GCs). GCs are an essential part of the treatment backbone for B-ALL, and GC resistance is a major clinical predictor of poor outcome. Elucidating the mechanisms of GC resistance in MLLr B-ALL is, therefore, critical to guide therapeutic strategies that deepen the response after induction therapy. Neuron-glial antigen-2 (NG2) expression is a hallmark of MLLr B-ALL and is minimally expressed in healthy hematopoietic cells. We recently reported that NG2 expression is associated with poor prognosis in MLLr B-ALL. Despite its contribution to MLLr B-ALL pathogenesis, the role of NG2 in MLLr-mediated leukemogenesis/chemoresistance remains elusive. Here, we show that NG2 is an epigenetically regulated direct target gene of the leukemic MLL-ALF transcription elongation factor 4 (AF4) fusion protein. NG2 negatively regulates the expression of the GC receptor nuclear receptor subfamily 3 group C member 1 (NR3C1) and confers GC resistance to MLLr B-ALL cells. Mechanistically, NG2 interacts with FLT3 to render ligand-independent activation of FLT3 signaling (a hallmark of MLLr B-ALL) and downregulation of NR3C1 via activating protein-1 (AP-1)-mediated transrepression. Collectively, our study elucidates the role of NG2 in GC resistance in MLLr B-ALL through FLT3/AP-1-mediated downregulation of NR3C1, providing novel therapeutic avenues for MLLr B-ALL.

B 细胞急性淋巴细胞白血病(B-ALL)是最常见的儿科癌症,长期总生存率约为 85%。然而,携带 MLL 基因(又称 KMT2A)重排的 B-ALL 被称为 MLLr B-ALL,常见于婴儿,且 5 年生存率较低 (
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引用次数: 0
Asciminib monotherapy as frontline treatment of chronic-phase chronic myeloid leukemia: results from the ASCEND study. 阿西米尼单药作为慢性期慢性髓性白血病的一线治疗:ASCEND研究结果
IF 21 1区 医学 Q1 HEMATOLOGY Pub Date : 2024-11-07 DOI: 10.1182/blood.2024024657
David T Yeung, Naranie Shanmuganathan, John Reynolds, Susan Branford, Mannu Walia, Agnes S M Yong, Jake Shortt, Lynette Chee, Nicholas Viiala, Ilona Cunningham, David M Ross, Alwyn D'Souza, Matthew Wright, Rosemary Harrup, Cecily Forsyth, Robin Filshie, Steven Lane, Peter Browett, Carolyn Grove, Andrew P Grigg, Timothy P Hughes

Abstract: Asciminib is a myristoyl site BCR::ABL1 inhibitor approved for patients with chronic-phase chronic myeloid leukemia (CP-CML) failing ≥2 prior lines of therapy. The Australasian Leukaemia and Lymphoma Group conducted the Asciminib Evaluation in Newly Diagnosed CML study to assess efficacy of asciminib for newly diagnosed CP-CML. Patients commenced asciminib 40 mg twice daily. Patients with treatment failure, defined as BCR::ABL1 of >10% at 3 or 6 months, or >1% at 12 or 18 months, received either imatinib, nilotinib, or dasatinib in addition to asciminib. In patients with suboptimal response, defined as levels of 1% to 10% at 6 months, >0.1% to 1% at 12 months, or >0.01% to 1% at 18 months, the asciminib dose was increased to 80 mg twice daily. With a median follow-up of 21 months (range, 0-36), 82 of 101 patients continue asciminib. Most common reasons for treatment discontinuation were adverse events (6%), loss of response (4%), and withdrawn consent (5%). There were no deaths; 1 patient developed lymphoid blast crisis. The coprimary end points were early molecular response (BCR::ABL1 of ≤10% at 3 months), achieved in 93% (96% confidence interval [CI], 86-97%), and major molecular response by 12 months achieved in 79%; (95% CI, 70-87%), respectively. Cumulative incidence of molecular response 4.5 was 53% by 24 months. One patient had 2 cerebrovascular events; no other arterial occlusive events were reported. Asciminib as frontline CP-CML therapy leads to high rates of molecular response with excellent tolerance and a low rate of discontinuation for toxicity. This trial was registered at https://www.anzctr.org.au/ as #ACTRN12620000851965.

Asciminib是一种肉豆蔻酰基位点BCR::ABL1抑制剂,已被批准用于既往接受过≥2种疗法的慢性期慢性髓性白血病(CP-CML)患者。澳大拉西亚白血病与淋巴瘤组织(ALLG)开展了 ASCEND 研究,以评估 asciminib 对新诊断的 CP-CML 的疗效。患者开始服用阿昔米尼 40 毫克,每天两次(BID),之后根据分子指标进行管理。治疗失败的患者(定义为 3 或 6 个月时 BCR::ABL1 >10% (IS),或 12 或 18 个月时 >1%)除接受阿昔米尼治疗外,还接受伊马替尼、尼洛替尼或达沙替尼治疗。对于反应不理想的患者,即6个月时反应水平为1%-10%、12个月时反应水平>0.1%-1%或18个月时反应水平>0.01%-1%的患者,阿昔米尼的剂量增加到80毫克,每日两次。中位随访 21 个月(0-36 个月),82/101 例患者继续服用阿昔米尼。最常见的治疗中止原因是不良事件(6%)、反应消失(4%)和撤回同意(5%)。无死亡病例;1 名患者在 6 个月时出现淋巴细胞凋亡危象。共同主要终点是早期分子反应(3个月时BCR::ABL1≤10%),93%的患者(96% CI 86-97%)实现了这一目标,12个月时主要分子反应的实现率分别为79%;(95% CI 69.7-86.8%)。到24个月时,MR4.5的累积发生率为53%。一名患者发生了2次脑血管事件;未报告其他动脉闭塞事件。阿西米尼作为CP-CML的一线疗法,分子反应率高,耐受性好,因毒性停药率低。(澳新临床试验注册中心 ACTRN12620000851965)。
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引用次数: 0
Epigenetic regulation of noncanonical menin targets modulates menin inhibitor response in acute myeloid leukemia. 非典型梅宁靶点的表观遗传调控调节急性髓性白血病的梅宁抑制剂反应
IF 21 1区 医学 Q1 HEMATOLOGY Pub Date : 2024-11-07 DOI: 10.1182/blood.2023023644
Xinyue Zhou, Lixia Zhang, Sajesan Aryal, Virginia Veasey, Amanda Tajik, Cecilia Restelli, Steven Moreira, Pengcheng Zhang, Yanfeng Zhang, Kristin J Hope, Yang Zhou, Changde Cheng, Ravi Bhatia, Rui Lu

Abstract: Menin inhibitors that disrupt the menin-MLL interaction hold promise for treating specific acute myeloid leukemia (AML) subtypes, including those with KMT2A rearrangements (KMT2A-r), yet resistance remains a challenge. Here, through systematic chromatin-focused CRISPR screens, along with genetic, epigenetic, and pharmacologic studies in a variety of human and mouse KMT2A-r AML models, we uncovered a potential resistance mechanism independent of canonical menin-MLL targets. We show that a group of noncanonical menin targets, which are bivalently cooccupied by active menin and repressive H2AK119ub marks, are typically downregulated after menin inhibition. Loss of polycomb repressive complex 1.1 (PRC1.1) subunits, such as polycomb group ring finger 1 (PCGF1) or BCL6 corepressor (BCOR), leads to menin inhibitor resistance by epigenetic reactivation of these noncanonical targets, including MYC. Genetic and pharmacological inhibition of MYC can resensitize PRC1.1-deficient leukemia cells to menin inhibition. Moreover, we demonstrate that leukemia cells with the loss of PRC1.1 subunits exhibit reduced monocytic gene signatures and are susceptible to BCL2 inhibition, and that combinational treatment with venetoclax overcomes the resistance to menin inhibition in PRC1.1-deficient leukemia cells. These findings highlight the important roles of PRC1.1 and its regulated noncanonical menin targets in modulating the menin inhibitor response and provide potential strategies to treat leukemia with compromised PRC1.1 function.

破坏 Menin-MLL 相互作用的 Menin 抑制剂有望治疗特定的急性髓性白血病亚型,包括 KMT2A 重排(KMT2A-r),但耐药性仍然是一个挑战。在这里,我们通过系统的染色质聚焦 CRISPR 筛选,以及在多种人类和小鼠 KMT2A-r AML 模型中进行的遗传学、表观遗传学和药理学研究,发现了一种独立于典型 Menin-MLL 靶点的潜在耐药机制。我们发现,一组非典型的 Menin 靶点(由活性 Menin 和抑制性 H2AK119ub 标记双价共占位)在 Menin 抑制后通常会下调。PCGF1 或 BCOR 等多聚核酸抑制复合体 1.1(PRC1.1)亚基的缺失会导致包括 MYC 在内的这些非经典靶点的表观遗传学再激活,从而导致 Menin 抑制剂耐药。遗传和药物抑制 MYC 可使 PRC1.1 缺失的白血病细胞对 Menin 抑制剂重新敏感。此外,我们还证明,缺失PRC1.1亚基的白血病细胞表现出单核细胞基因特征的减少,并易受BCL2抑制作用的影响,而venetoclax的联合治疗可克服PRC1.1缺陷白血病细胞对Menin抑制作用的耐药性。这些发现凸显了PRC1.1及其调控的非经典Menin靶点在调节Menin抑制剂反应中的重要作用,并为治疗PRC1.1功能受损的白血病提供了潜在的策略。
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引用次数: 0
Raab MS, Breitkreutz I, Tonon G, et al. Targeting PKC: a novel role for beta-catenin in ER stress and apoptotic signaling. Blood. 2009;113(7):1513-1521. Raab MS、Breitkreutz I、Tonon G 等:靶向 PKC:β-catenin 在 ER 应激和细胞凋亡信号转导中的新作用。血液。2009;113(7):1513-1521.
IF 21 1区 医学 Q1 HEMATOLOGY Pub Date : 2024-11-07 DOI: 10.1182/blood.2024026968
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引用次数: 0
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