Seminars in hematology最新文献

英文中文

A Call to Arms: Overcoming challenges in Myelodysplastic Syndromes therapy advances 武器的召唤：克服骨髓增生异常综合症治疗进展中的挑战。

IF 5 3区医学 Q1 HEMATOLOGY

Seminars in hematology

Pub Date : 2024-12-01 DOI: 10.1053/j.seminhematol.2024.11.005

Kathy L. McGraw , Peter D. Aplan , Steven Z. Pavletic

引用次数: 0

Cellular and immunotherapies for myelodysplastic syndromes 骨髓增生异常综合征的细胞和免疫疗法。

IF 5 3区医学 Q1 HEMATOLOGY

Seminars in hematology

Pub Date : 2024-12-01 DOI: 10.1053/j.seminhematol.2024.09.006

Ryan J. Stubbins , Hannah Cherniawsky , Aly Karsan

In this review article, we outline the current landscape of immune and cell therapy-based approaches for patients with myelodysplastic syndromes (MDS). Given the well characterized graft-versus-leukemia (GVL) effect observed with allogeneic hematopoietic cell transplantation, and the known immune escape mechanisms observed in MDS cells, significant interest exists in developing immune-based approaches to treat MDS. These attempts have included antibody-based drugs that block immune escape molecules, such as inhibitors of the PD-1/PD-L1 and TIM-3/galectin-9 axes that mediate interactions between MDS cells and T-lymphocytes, as well as antibodies that block the CD47/SIRPα interaction, which mediates macrophage phagocytosis. Unfortunately, these approaches have been largely unsuccessful. There is significant potential for T-cell engaging therapies and chimeric antigen receptor T (CAR-T) cells, but there are also several limitations to these approaches that are unique to MDS. However, many of these limitations may be overcome by the next generation of cellular therapies, including those with engineered T-cell receptors or natural killer (NK)-cell based platforms. Regardless of the approach, all these immune cells are subject to the complex bone marrow microenvironment in MDS, which harbours a variable and heterogeneous mix of pro-inflammatory cytokines and immunosuppressive elements. Understanding this interaction will be paramount to ensuring the success of immune and cellular therapies in MDS.

在这篇综述文章中，我们概述了目前治疗骨髓增生异常综合征（MDS）患者的基于免疫和细胞疗法的方法。鉴于同种异体造血细胞移植中观察到的移植物抗白血病（GVL）效应以及在 MDS 细胞中观察到的已知免疫逃逸机制，人们对开发基于免疫的方法来治疗 MDS 产生了浓厚的兴趣。这些尝试包括阻断免疫逃逸分子的抗体药物，如介导 MDS 细胞与 T 淋巴细胞相互作用的 PD-1/PD-L1 和 TIM-3/galectin-9 轴抑制剂，以及阻断介导巨噬细胞吞噬作用的 CD47/SIRPα 相互作用的抗体。遗憾的是，这些方法基本上都不成功。T细胞参与疗法和嵌合抗原受体T（CAR-T）细胞具有巨大的潜力，但这些方法也存在一些MDS特有的局限性。不过，下一代细胞疗法（包括具有工程T细胞受体或基于自然杀伤（NK）细胞平台的疗法）可能会克服其中的许多局限性。无论采用哪种方法，所有这些免疫细胞都会受到 MDS 复杂骨髓微环境的影响，因为骨髓微环境中存在着多种多样的促炎细胞因子和免疫抑制因子。了解这种相互作用对于确保 MDS 免疫疗法和细胞疗法的成功至关重要。

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引用次数: 0

Understanding MDS stem cells: Advances and limitations 了解 MDS 干细胞：进展与局限。

IF 5 3区医学 Q1 HEMATOLOGY

Seminars in hematology

Pub Date : 2024-12-01 DOI: 10.1053/j.seminhematol.2024.09.007

Sweta B. Patel , Daniel R. Moskop , Craig T. Jordan, Eric M. Pietras

In work spanning several decades, extensive studies have focused on the properties of malignant stem cells that drive the pathogenesis of acute myeloid leukemia (AML). However, relatively little attention has been devoted to several serious myeloid malignancies that occur prior to the onset of frank leukemia, including myelodysplastic syndrome (MDS). Like leukemia, MDS is hypothesized to arise from a pool of immature malignant stem and progenitor cells (MDS-SCs) that serve as a reservoir for disease evolution and progression¹. While multiple studies have sought to identify and characterize the biology and vulnerabilities of MDS-SCs, yet translation of scientific concepts to therapeutically impactful regimens has been limited. Here, we evaluate the currently known properties of MDS-SCs as well as the post-transcriptional mechanisms that drive MDS pathogenesis at a stem and progenitor level. We highlight limits and gaps in our characterization and understanding of MDS-SCs and address the extent to which the properties of MDS-SC are (and can be) inferred from the characterization of LSCs.

在长达数十年的工作中，大量研究都集中在驱动急性髓性白血病（AML）发病机制的恶性干细胞特性上。然而，人们对几种严重骨髓恶性肿瘤的关注相对较少，这些恶性肿瘤发生在白血病发病之前，包括骨髓增生异常综合征（MDS）。与白血病一样，骨髓增生异常综合症也被认为是由未成熟的恶性干细胞和祖细胞（MDS-SCs）引起的，这些细胞是疾病演变和发展的蓄水池1。虽然已有多项研究试图确定和描述MDS-SCs的生物学特性和脆弱性，但将科学概念转化为具有治疗效果的治疗方案的工作还很有限。在此，我们评估了目前已知的MDS-SCs特性，以及在干细胞和祖细胞水平上驱动MDS发病的转录后机制。我们强调了我们对MDS-SC特性描述和理解的局限性和差距，并探讨了从LSC特性描述中推断MDS-SC特性的程度（以及可以推断的程度）。

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引用次数: 0

Implications for metabolic disturbances in myelodysplastic syndromes 骨髓增生异常综合征代谢紊乱的影响。

IF 5 3区医学 Q1 HEMATOLOGY

Seminars in hematology

Pub Date : 2024-12-01 DOI: 10.1053/j.seminhematol.2024.11.004

Kathy L. McGraw , Daniel R. Larson

The Myelodysplastic Syndromes (MDS) are heterogeneous stem cell malignancies clinically characterized by bone marrow dysplasia, peripheral blood cytopenias, and a high risk for transformation to acute myeloid leukemia. In early stages of disease, differentiation defects and maturation blocks result in deficient hematopoiesis. In higher risk disease, unrestricted proliferation of immature blast cells leads to leukemogenesis. Disease pathogenesis can be attributed to many factors including chronic inflammation that is driven in part by commonly found somatic gene mutations (SGM) fostering expansion of malignant clones while suppressing normal hematopoiesis. Cellular metabolism that both directly and indirectly regulates hematopoietic stem cell (HSC) fate, is intimately connected to the immune system, is altered by MDS somatic gene mutations and is likely is a major contributor to disease pathophysiology. Despite this likely role in pathobiology, there is an underwhelming depth of literature on the subject and the precise metabolic dysregulations in these myeloid malignancies have yet to be fully delineated. In this review, we will provide a general overview of several major metabolic processes and how each directs HSC fate, provide a summary of metabolic studies in MDS, discuss how common SGM and inflammation influence metabolic pathways to drive bone marrow failure, and end with a discussion of standards of care and how these should be carefully considered in the context of metabolic dysregulation.

骨髓增生异常综合征（MDS）是一种异质性干细胞恶性肿瘤，临床特点是骨髓发育不良、外周血细胞减少以及极易转化为急性髓性白血病。在疾病的早期阶段，分化缺陷和成熟障碍会导致造血功能缺陷。在高风险疾病中，未成熟的胚泡细胞不受限制地增殖会导致白血病的发生。疾病的发病机制可归因于多种因素，其中包括慢性炎症，而慢性炎症的部分驱动因素是常见的体细胞基因突变（SGM），这种突变在抑制正常造血的同时促进了恶性克隆的扩增。细胞代谢直接或间接调控造血干细胞（HSC）的命运，与免疫系统密切相关，MDS体细胞基因突变改变了细胞代谢，很可能是疾病病理生理学的主要因素。尽管MDS在病理生物学中可能起着重要作用，但有关这一主题的文献深度却远远不够，而且这些髓系恶性肿瘤中确切的代谢失调尚未完全阐明。在这篇综述中，我们将概述几种主要的代谢过程以及每种代谢过程如何引导造血干细胞的命运，总结 MDS 中的代谢研究，讨论常见的 SGM 和炎症如何影响代谢途径以导致骨髓衰竭，最后讨论护理标准以及如何在代谢失调的背景下仔细考虑这些标准。

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引用次数: 0

Patient-reported outcomes in early phase trials for patients with myelodysplastic syndromes 骨髓增生异常综合征患者早期试验中的患者报告结果。

IF 5 3区医学 Q1 HEMATOLOGY

Seminars in hematology

Pub Date : 2024-12-01 DOI: 10.1053/j.seminhematol.2024.10.010

Tito Mendoza , Amanda L. King , Elizabeth Vera , Alain Mina , Kathy McGraw , Steven Pavletic , Terri S. Armstrong

Patients with myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) experience a wide range of symptoms due both to their underlying disease and the effects of treatment. Designing early phase trials to explore effective therapies in these patients should not only examine anti-tumor activity, but also consider the effects of treatments on how patients feel and function. Assessing symptomatic toxicities associated with new therapies in early phase trials from the patient perspective is best measured using patient-reported outcomes (PROs) and offers valuable insight and complementary information to the traditional adverse event reporting in cancer clinical trials. This review describes PROs, highlights their importance in MDS drug development, and outlines the key psychometric properties and practical considerations that make PROs essential and desirable in evaluating the impact of new therapies. We will provide a general overview of PROs and follow with application of PROs in MDS/AML including strategies to be considered in early phase trials. Finally, we describe the creation of the Office of Patient-Centered Outcomes Research at the US National Institutes of Health which has developed a standardized PROs methodology for early phase trials conducted in the Center for Cancer Research at the US National Cancer Institute.

骨髓增生异常综合征（MDS）或急性髓性白血病（AML）患者会因潜在疾病和治疗效果而出现各种症状。在设计早期试验以探索针对这些患者的有效疗法时，不仅要检查抗肿瘤活性，还要考虑治疗对患者感觉和功能的影响。从患者的角度评估早期试验中与新疗法相关的症状性毒性，最好使用患者报告的结果（PROs）来衡量，它为癌症临床试验中传统的不良事件报告提供了宝贵的见解和补充信息。本综述介绍了患者报告结果，强调了其在 MDS 药物开发中的重要性，并概述了使患者报告结果成为评估新疗法影响的关键和理想方法的关键心理测量学特性和实际考虑因素。我们将对PROs进行总体概述，然后介绍PROs在MDS/AML中的应用，包括在早期阶段试验中需要考虑的策略。最后，我们将介绍美国国立卫生研究院（US National Institutes of Health）设立的以患者为中心的结果研究办公室（Office of Patient-Centered Outcomes Research），该办公室为美国国立癌症研究所（US National Cancer Institute）癌症研究中心（Center for Cancer Research）开展的早期试验制定了标准化的PROs方法。

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引用次数: 0

RNA splicing as a therapeutic target in myelodysplastic syndromes 将 RNA 剪接作为骨髓增生异常综合征的治疗靶点。

IF 5 3区医学 Q1 HEMATOLOGY

Seminars in hematology

Pub Date : 2024-12-01 DOI: 10.1053/j.seminhematol.2024.10.005

Chun-Chih Tseng, Esther A. Obeng

Myelodysplastic syndromes (MDS) represent a heterogeneous group of hematological disorders and are more commonly found in people over the age of 60. MDS patients exhibit peripheral blood cytopenias and carry an increased risk of disease progression to acute myeloid leukemia (AML). Splicing factor mutations (including genes SF3B1, SRSF2, U2AF1, and ZRSR2) are early events identified in more than 50% of MDS cases. These mutations cause aberrant pre-mRNA splicing and impact MDS pathophysiology. Emerging evidence shows that splicing factor-mutant cells are more sensitive to perturbations targeting the spliceosome, aberrantly spliced genes and/or their regulated molecular pathways. This review summarizes current therapeutic strategies and ongoing efforts targeting splicing factor mutations for the treatment of MDS.

骨髓增生异常综合征（MDS）是一类异质性血液病，多见于 60 岁以上的人群。骨髓增生异常综合征患者表现为外周血细胞减少，疾病进展为急性髓性白血病（AML）的风险增加。剪接因子突变（包括基因 SF3B1、SRSF2、U2AF1 和 ZRSR2）是在 50% 以上 MDS 病例中发现的早期事件。这些突变会导致前 mRNA 剪接异常，并影响 MDS 的病理生理学。新的证据显示，剪接因子突变细胞对针对剪接体、异常剪接基因和/或其调控分子通路的干扰更敏感。本综述总结了目前针对剪接因子突变治疗 MDS 的治疗策略和正在进行的工作。

引用次数: 0

Therapy-related myelodysplastic syndromes and acute myeloid leukemia 与治疗相关的骨髓增生异常综合征和急性髓性白血病。

IF 5 3区医学 Q1 HEMATOLOGY

Seminars in hematology

Pub Date : 2024-12-01 DOI: 10.1053/j.seminhematol.2024.09.004

Sangeetha Venugopal , Amy E. DeZern

Progress always comes at a price: the field of oncology has seen unprecedented progress in treatment options recently for many solid and hematologic cancers. Unfortunately, these long-term survivors of prior cancer and cytotoxic therapy exposure are at higher risk of therapy-related myelodysplastic syndromes/acute myeloid leukemia (t-MDS/AML.) T-MDS/AML is a myeloid malignancy which occur after exposure to chemotherapy or radiation therapy for unrelated malignancy. T-MDS/AML is associated with adverse cytogenomic features and poor prognosis. While advances in the field of clonal hematopoiesis and germline variants has unraveled the molecular underpinnings of t-MDS/AML, we have miles to go in terms of t-MDS/AML directed therapy and improvement in outcomes. In this review, we discuss the epidemiology of t-MDS/AML, clinical and biological insights, evolution of t-MDS/AML and available treatment options.

进步总是要付出代价的：近来，肿瘤学领域在许多实体癌和血液肿瘤的治疗方案上取得了前所未有的进展。不幸的是，这些曾接受过癌症和细胞毒治疗的长期幸存者罹患与治疗相关的骨髓增生异常综合征/急性髓性白血病（t-MDS/AML）的风险较高。T-MDS/AML与不良细胞基因组特征和不良预后有关。虽然克隆造血和种系变异领域的研究进展已经揭示了t-MDS/AML的分子基础，但在t-MDS/AML的定向治疗和改善预后方面，我们还有很长的路要走。在这篇综述中，我们将讨论 t-MDS/AML 的流行病学、临床和生物学见解、t-MDS/AML 的演变以及现有的治疗方案。

引用次数: 0

FaMMily Affairs: Dissecting inherited contributions to multiple myeloma risk. 家族事务：剖析遗传因素对多发性骨髓瘤风险的影响。

IF 5 3区医学 Q1 HEMATOLOGY

Seminars in hematology

Pub Date : 2024-11-30 DOI: 10.1053/j.seminhematol.2024.11.006

Saoirse Bodnar, Tehilla Brander, Julie Gold, Ayuko Iverson, Alessandro Lagana, Kenan Onel, Sundar Jagannath, Samir Parekh, Santiago Thibaud

Etiological links to multiple myeloma (MM) remain poorly understood, though emerging evidence suggests a significant hereditary component. This review integrates current literature on inherited factors contributing to MM risk, synthesizing both epidemiologic and genomic data. We examine familial clustering patterns, assess genome-wide association studies (GWAS) that reveal common genetic variants linked to MM, and explore rare, high-penetrance variants in key susceptibility genes. Additionally, we advocate for routine germline screening in high-risk MM populations, particularly those with a strong family history of cancer, a personal history of cancer, or early-onset disease. By elucidating the inherited influences on MM predisposition, this review seeks to inform future research and refine risk assessment strategies in this population.

多发性骨髓瘤（MM）的病因学联系仍然知之甚少，尽管新出现的证据表明其具有重要的遗传成分。这篇综述整合了目前关于遗传因素导致MM风险的文献，综合了流行病学和基因组数据。我们研究了家族聚类模式，评估了揭示与MM相关的常见遗传变异的全基因组关联研究（GWAS），并探索了关键易感基因中罕见的高外显率变异。此外，我们提倡在高风险MM人群中进行常规生殖系筛查，特别是那些有强烈的癌症家族史、个人癌症史或早发性疾病的人群。通过阐明遗传因素对MM易感性的影响，本综述旨在为未来的研究提供信息，并完善该人群的风险评估策略。

引用次数: 0

The potential promise of machine learning in myelodysplastic syndrome. 机器学习在骨髓增生异常综合征中的潜在前景。

IF 5 3区医学 Q1 HEMATOLOGY

Seminars in hematology

Pub Date : 2024-11-16 DOI: 10.1053/j.seminhematol.2024.11.002

Valeria Visconte, Jaroslaw P Maciejewski, Luca Guarnera

The introduction of artificial intelligence (AI), and in particular machine learning (ML), has revolutionized biomedical research at the clinical level, a trend that also includes hematologic malignancies and myeloid neoplasia (MN). ML encompasses a wide range of applications such as enhanced diagnostics, outcome predictions, decision trees and clustering. Despite several reports in recent years and the achievement of promising results, none of the ML-based pipelines have been directly translated into clinical practice. ML offers the potential to help refine risk stratification and increase accuracy to correctly predict clinical outcomes and disease classification. One of the complications in the clinical utilization of ML is that a large percentage of hematologists have limited familiarity with these tools which can cause skepticism. Concerns have also been raised by patients that are worried about privacy issues, reliability of the outcomes, and loss of human interaction. In this review, we aim to pinpoint the main mechanisms and applications of ML, as well as application in MN and Myelodysplastic Syndrome, highlighting strengths and limitations, and addressing the potential promise in clinical implementation of ML-pipelines.

人工智能（AI），特别是机器学习（ML）的引入，已经彻底改变了临床层面的生物医学研究，这一趋势也包括血液恶性肿瘤和髓系肿瘤（MN）。机器学习涵盖了广泛的应用，如增强诊断，结果预测，决策树和聚类。尽管近年来有几篇报道并取得了可喜的成果，但没有一种基于ml的管道直接转化为临床实践。ML提供了帮助完善风险分层和提高准确性的潜力，以正确预测临床结果和疾病分类。临床应用ML的并发症之一是大部分血液学家对这些工具的熟悉程度有限，这可能会引起怀疑。患者也提出了担忧，他们担心隐私问题、结果的可靠性以及人际交往的丧失。在这篇综述中，我们旨在明确ML的主要机制和应用，以及在MN和骨髓增生异常综合征中的应用，强调ML管道的优势和局限性，并解决ML管道在临床实施中的潜在前景。

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引用次数: 0

Immunocompetent mouse models of multiple myeloma. 免疫功能正常的多发性骨髓瘤小鼠模型。

IF 5 3区医学 Q1 HEMATOLOGY

Seminars in hematology

Pub Date : 2024-11-16 DOI: 10.1053/j.seminhematol.2024.11.003

Peter Leif Bergsagel, Marta Chesi

Immunocompetent murine models of multiple myeloma are critical for understanding the pathogenesis of multiple myeloma and for the development of novel immunotherapeutics. Different models are available in Balb/c and C57Bl strains, each with different advantages and disadvantages. The availability of many transplantable cell lines allows for the conduct of experiments with large cohorts of mice bearing identical tumors, while cell lines that grow in vitro can be used for genetic manipulations. The introduction of human CRBN into these models allows for the study of IMiDs and cereblon based PROTACs in mice. New genetically engineered models based on germinal center cell activation of Nsd2 or Ccnd1 together with constitutive NFkB are being developed to model some of the important genetic subtypes of human multiple myeloma.

免疫功能健全的多发性骨髓瘤小鼠模型对于了解多发性骨髓瘤的发病机制和开发新型免疫疗法至关重要。Balb/c和C57Bl品系有不同的模型，各有利弊。有了许多可移植的细胞系，就可以用携带相同肿瘤的大批小鼠进行实验，而体外生长的细胞系则可用于遗传操作。在这些模型中引入人类 CRBN，可以在小鼠中研究 IMiDs 和基于脑隆的 PROTACs。目前正在开发基于生殖中心细胞激活 Nsd2 或 Ccnd1 以及组成型 NFkB 的新基因工程模型，以模拟人类多发性骨髓瘤的一些重要遗传亚型。

引用次数: 0

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