Experimental hematology最新文献_第3页

Polycomb repressive complexes as therapeutic targets in hematologic malignancies 多梳抑制复合物作为血液系统恶性肿瘤的治疗靶点。

IF 2.1 4区医学 Q2 HEMATOLOGY

Experimental hematology

Pub Date : 2025-12-22 DOI: 10.1016/j.exphem.2025.105339

Makoto Yamagishi , Atsushi Iwama , Issay Kitabayashi

Polycomb-group proteins form PRC1 and PRC2 complexes that mediate heritable transcriptional repression via H2AK119 ubiquitination and H3K27 trimethylation. Canonical PRC1 catalyzes H2AK119 monoubiquitination through RING1A/B, whereas PRC2 deposits H3K27me3 via EZH1/2. Variant PRC1 (vPRC1) and PRC2 subtypes use distinct recruitment mechanisms, enabling both PRC2-dependent and -independent silencing. In hematopoiesis, components of PRC1, such as BMI1, and those of PRC1.1, including BCOR and PCGF1, have been well characterized for their roles in governing hematopoietic stem cell (HSC) self-renewal and lineage specification. Similarly, PRC2 components, particularly EZH1/2, SUZ12, and EED, are essential for the maintenance of HSCs. Aberrations in PRC1/2, such as gain- or loss-of-function mutations in EZH2 and loss-of-function mutations in BCOR, drive hematologic malignancies, including acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and lymphomas. In malignant lymphoma, mutations in chromatin regulators (e.g., EZH2, KMT2D, and CREBBP) reshape the epigenetic landscape, disrupting differentiation and immune recognition. Elevated H3K27me3 represents an early and shared epigenetic feature across diverse subclones in lymphoid neoplasms, including adult T-cell leukemia/lymphoma (ATL). Therapeutic targeting of H3K27me3 with EZH2-selective inhibitors such as tazemetostat has shown clinical benefit in lymphoma; however, their efficacy is limited by functional redundancy with EZH1. The dual EZH1/2 inhibitor valemetostat overcomes this limitation by reactivating tumor-suppressor genes, achieving durable responses in ATL and peripheral T-cell lymphoma (PTCL). Nonetheless, therapeutic resistance can emerge through PRC2 gatekeeper mutations and compensatory DNA methylation. These findings underscored the value of targeting the dysregulated epigenome and support the continued clinical development of dual EZH1/2 inhibitors.

Polycomb group （PcG）蛋白形成多亚基Polycomb抑制复合物（PRC1和PRC2），通过组蛋白修饰介导可遗传的转录抑制。典型的PRC1通过RING1A/B催化H2AK119单泛素化，而PRC2通过EZH1/2沉积H3K27me3。变体PRC1 （vPRC1）和PRC2亚型采用不同的招募机制，使PRC2依赖性和非依赖性沉默成为可能。在造血过程中，PRC1的组成部分，如BMI1，以及PRC1.1的组成部分，包括BCOR和PCGF1，已经被很好地表征为它们在控制造血干细胞（HSC）自我更新和谱系规范中的作用。同样，PRC2成分，特别是EZH1/2、SUZ12和EED，对于维持造血干细胞至关重要。PRC1/2的畸变，如EZH2的功能获得或丧失突变和bor的功能丧失突变，驱动包括AML、MDS和淋巴瘤在内的血液系统恶性肿瘤。在恶性淋巴瘤中，染色质调节因子（如EZH2、KMT2D、CREBBP）的突变重塑了表观遗传格局，破坏了分化和免疫识别。H3K27me3的升高代表了淋巴样肿瘤（包括成人t细胞白血病/淋巴瘤（ATL））中不同亚克隆的早期和共同的表观遗传特征。靶向治疗H3K27me3的ezh2选择性抑制剂如他zemetostat在淋巴瘤中显示出临床益处；然而，它们的功效受到EZH1功能冗余的限制。双EZH1/2抑制剂valemetostat通过重新激活肿瘤抑制基因克服了这一限制，在ATL和周围t细胞淋巴瘤（PTCL）中实现了持久的应答。尽管如此，治疗抗性可以通过PRC2看门人突变和补偿性DNA甲基化出现。这些发现强调了靶向失调表观基因组的价值，并支持双EZH1/2抑制剂的持续临床开发。

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引用次数: 0

Splenic Erythroblasts Fuels Leukemia Progression Through Metabolic Crosstalk 脾母红细胞通过代谢串扰促进白血病进展。

IF 2.1 4区医学 Q2 HEMATOLOGY

Experimental hematology

Pub Date : 2025-12-15 DOI: 10.1016/j.exphem.2025.105351

Jin Wang , Jian Xu

A recent study by Li et al. reveals a previously unrecognized erythroid cell population in the AML spleen that actively promotes leukemia growth through cytokine signaling and metabolic reprogramming

Li等人最近的一项研究揭示了AML脾脏中一种以前未被识别的红系细胞群，它通过细胞因子信号传导和代谢重编程积极促进白血病的生长。

引用次数: 0

Loss of Ezh2 precipitates lethal disease progression in a mouse model of Calr-mutated myeloproliferative neoplasms 在calr突变的骨髓增殖性肿瘤小鼠模型中，Ezh2的缺失加速了致命的疾病进展。

IF 2.1 4区医学 Q2 HEMATOLOGY

Experimental hematology

Pub Date : 2025-12-13 DOI: 10.1016/j.exphem.2025.105350

Koki Ueda , Yuka Sato , Keiji Minakawa , Saori Miura , Yuko Hashimoto , Kazuhiko Ikeda

Patients with CALR-mutant essential thrombocythemia (ET), the myeloproliferative neoplasm (MPN) subtype with the most favorable long-term prognosis, remain at risk of developing secondary myelofibrosis (sMF) or acute myeloid leukemia (AML). Outcomes after such progression are poor. Loss-of-function mutations in the epigenetic regulator EZH2 are frequently acquired during disease evolution, but their causal contribution to CALR-driven MPN has remained uncertain. To investigate this question, we used a knock-in mouse that constitutively expresses a Calr frameshift allele and introduced conditional Ezh2 deletion triggered by tamoxifen. Ezh2 loss in Calr-mutant MPN resulted in lethal disease progression. These mice developed two terminal outcomes that mirror human disease: fibrotic MPN (sMF-like) and blast-phase MPN (AML-like). Transplantation experiments demonstrated that only the AML-like phenotype was transplantable, whereas the sMF-like phenotype did not confer lethal condition in recipients. These findings provide direct in vivo evidence that EZH2 loss drives malignant evolution of CALR-mutant MPN. Transcriptomic profiling of leukemic stem cells from AML-like mice revealed enrichment of fatty acid oxidation (FAO) pathways. Short-term colony assays showed that inhibition of peroxisome proliferator-activated receptor-γ (PPARγ) modestly increased the antiproliferative effect of cytarabine on AML-derived stem and progenitor cells, suggesting a possible reliance on FAO. Reanalysis of public single-cell RNA-sequencing data from patients with MPN progressing to AML also demonstrated elevated FAO signatures in leukemic stem cells. Together, these results identify EZH2 loss as a key determinant of CALR-mutant MPN progression and point to altered metabolic wiring as a potential vulnerability in post-MPN AML.

calr突变型原发性血小板增多症（ET）患者是具有最有利长期预后的骨髓增生性肿瘤（MPN）亚型，但仍有发生继发性骨髓纤维化（sMF）或急性髓系白血病（AML）的风险。这种进展后的结果很差。表观遗传调控因子EZH2的功能丧失突变经常在疾病进化过程中获得，但它们对calr驱动的MPN的因果贡献仍然不确定。为了研究这个问题，我们使用了表达Calr移码等位基因的敲入小鼠，并引入了由他莫昔芬触发的条件Ezh2缺失。在calr突变的MPN中Ezh2缺失导致致命的疾病进展。这些小鼠出现了两种反映人类疾病的终末结果：纤维化性MPN （smf样）和胚期MPN （aml样）。移植实验表明，只有aml样表型可移植，而smf样表型不会导致受体死亡。这些发现为EZH2缺失驱动calr突变型MPN的恶性进化提供了直接的体内证据。aml样小鼠白血病干细胞的转录组学分析揭示了脂肪酸氧化（FAO）途径的富集。短期集落试验显示，抑制PPARγ可适度增加阿糖胞苷对aml衍生的干细胞和祖细胞的抗增殖作用，这表明可能依赖于FAO。对MPN进展为AML患者的公开单细胞rna测序数据的重新分析也表明，白血病干细胞中的FAO特征升高。总之，这些结果确定EZH2缺失是calr突变型MPN进展的关键决定因素，并指出代谢线路的改变是MPN后AML的潜在脆弱性。摘要：calr突变的骨髓增殖性肿瘤偶尔会发展为继发性骨髓纤维化或急性髓系白血病，但共同发生的EZH2丢失的作用尚不清楚。使用具有诱导Ezh2缺失的calr突变敲入小鼠，我们显示了smf样或aml样致命疾病的年龄依赖性进化。在非关键阶段，外周血计数保持接近正常，而骨髓HSPC区室已经扭曲。aml样而非smf样，Flk2- CD48+ LSK细胞传递白血病并表现出增强的脂肪酸氧化特征，这表明一种独特的、潜在的靶向代谢偏倚。

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引用次数: 0

Hematopoietic stem cell-independent and -dependent hematopoiesis: new insights and lineage-tracing methods 造血干细胞独立和依赖造血：新的见解和谱系追踪方法。

IF 2.1 4区医学 Q2 HEMATOLOGY

Experimental hematology

Pub Date : 2025-12-13 DOI: 10.1016/j.exphem.2025.105352

Miguel Ganuza , Momoko Yoshimoto

Recent advances in developmental hematology have revealed unappreciated hematopoietic waves and origins during development, and unexpected hematopoietic stem cell (HSC)-independent progenitors that provide lifelong hematopoiesis, using in vivo barcoding technologies and various lineage-tracing mouse models. Also, these tools estimate HSC numbers and display HSC behaviors that have not been anticipated. This review introduces such new discoveries in blood development and discusses the data and controversies.

发育血液学的最新进展揭示了发育过程中未被认识到的造血波和起源，以及意想不到的造血干细胞（HSC）独立祖细胞，这些祖细胞提供终身造血，使用体内条形码技术和各种谱系追踪小鼠模型。此外，这些工具估计HSC数量并显示未预料到的HSC行为。本文介绍了这些在血液发育方面的新发现，并讨论了数据和争议。摘要：利用体内条形码和各种谱系追踪小鼠模型等前沿方法，发育血液学的最新进展揭示了胚胎中以前未被认识的造血波和起源，包括意想不到的hsc独立祖细胞，这些祖细胞有助于终身造血。这些工具还确定了造血细胞、早期红细胞和巨核细胞分化途径，估计了HSC数量，并揭示了围产期未预料到的HSC行为。总之，这些见解正在重塑我们造血的基本概念并改变范式。

引用次数: 0

Mixed-lineage leukemia cells undergo unique adaptations in the CNS niche 混合谱系白血病细胞在中枢神经系统生态位中经历独特的适应。

IF 2.1 4区医学 Q2 HEMATOLOGY

Experimental hematology

Pub Date : 2025-12-08 DOI: 10.1016/j.exphem.2025.105347

Alasdair Duguid , Camille Malouf , Leslie Nitsche , Christina Halsey , Katrin Ottersbach

KMT2A-rearranged (KMT2A-r) infant leukemia can present as a lymphoid, myeloid, or mixed-lineage leukemia and frequently involves the central nervous system (CNS); yet, the impact of this lineage diversity and plasticity on CNS involvement remains poorly understood. Using a fully murine immunocompetent model of KMT2A-AFF1+ mixed-lineage infant leukemia, we investigated how the CNS niche influences the phenotype and function of leukemia propagating cells (LPCs). Previously defined bone marrow (BM)–derived LPCs were transplanted and shown to engraft the CNS, although not equally; lineage-negative cKit+ common lymphoid progenitor cells were consistently underrepresented in the niche. Transplants of CNS-derived LPCs, modelling relapse, demonstrated reduced systemic repopulation capacity, with many recipients exhibiting stable long-term engraftment without developing overt leukemia, a phenomenon not observed in BM-derived transplants. Transcriptomic profiling of matched CNS- and BM-derived LPCs revealed enrichment of pathways involved in hypoxia, lipid and cholesterol homeostasis, and inflammatory signaling in the CNS. Notably, LPC subsets that successfully adapted to the CNS niche upregulated lipid and fatty acid metabolic programs. CNS-derived LPCs showed increased expression of genes involved in T cell immune modulation, suggesting a skew to a more immunosuppressive environment. These findings indicate that the CNS niche imposes selective pressures that cause lasting metabolic and functional reprogramming of leukemic cells, impairing their ability to reestablish systemic disease and potentially affecting immune cell interactions. Furthermore, these findings may be more generally relevant to primary mixed-lineage infant leukemia and, increasingly important, lineage-switched infant leukemia.

kmt2a -重排（KMT2A-r）婴儿白血病可以表现为淋巴细胞、髓细胞或混合谱系白血病，并经常累及中枢神经系统（CNS），但这种谱系多样性和可塑性对中枢神经系统累及的影响尚不清楚。利用KMT2A-AFF1+混合谱系婴儿白血病的全小鼠免疫活性模型，我们研究了中枢神经系统生态位如何影响白血病繁殖细胞（LPC）的表型和功能。先前定义的骨髓（BM）来源的LPCs被移植，并被证明可以移植中枢神经系统，尽管不是完全一样；谱系阴性的cKit+普通淋巴样祖细胞在生态位中的代表性一直不足。中枢神经系统来源的LPCs移植，模拟复发，显示出系统再生能力降低，许多受者表现出稳定的长期植入，没有出现明显的白血病，这一现象在脑转移来源的移植中没有观察到。匹配的CNS和bm来源的LPCs的转录组学分析显示，CNS中参与缺氧、脂质和胆固醇稳态以及炎症信号传导的途径富集。值得注意的是，成功适应中枢神经系统生态位的LPC亚群上调了脂质和脂肪酸代谢程序。cns衍生的LPCs显示参与T细胞免疫调节的基因表达增加，表明偏向于更免疫抑制的环境。这些发现表明，中枢神经系统生态位施加选择性压力，导致白血病细胞持续的代谢和功能重编程，损害其重建全身性疾病的能力，并可能影响免疫细胞的相互作用。此外，这些发现可能更普遍地与原发性混合谱系婴儿白血病和越来越重要的谱系切换婴儿白血病有关。

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引用次数: 0

Emerging paradigms in redox regulation: the role of selenoproteins in normal and malignant hematopoiesis 氧化还原调控的新范式：硒蛋白在正常和恶性造血中的作用。

IF 2.1 4区医学 Q2 HEMATOLOGY

Experimental hematology

Pub Date : 2025-12-07 DOI: 10.1016/j.exphem.2025.105346

Yumi Aoyama , Hiromi Yamazaki , Daichi Inoue

Selenoproteins—a unique class of antioxidant enzymes characterized by the incorporation of selenocysteine at their catalytic core—function as pivotal regulators of redox homeostasis in hematopoiesis. This review elucidates how selenoprotein-mediated redox control orchestrates hematopoietic stem cell (HSC) fate decisions, maintaining the critical balance between self-renewal and differentiation. The glutathione peroxidase (GPX) family, particularly GPX1 and GPX4, plays indispensable roles in hydrogen peroxide detoxification and protection against lipid peroxidation-induced ferroptotic cell death, respectively. Similarly, thioredoxin reductases (TXNRDs) sustain critical redox equilibrium via thioredoxin regeneration. Recent studies demonstrate that these redox regulators facilitate the proliferation and differentiation of HSCs and mature lineages. Selenoprotein deficiency disrupts HSC fitness, impairs B- and erythroid-lineage maturation, and induces B-to-myeloid lineage switching—pathogenic features observed in aged hematopoiesis, highlighting the critical roles of selenoproteins in balanced, healthy hematopoiesis. Emerging evidence demonstrates that leukemic cells also exploit selenoprotein pathways to mitigate oxidative stress, suggesting that selective modulation of specific selenoproteins may constitute a promising therapeutic approach, provided we delineate their differential utilization between normal and malignant hematopoiesis. Selenoproteins function at the intersection of several transcriptional networks, including NRF2, whose orchestrated antioxidant responses may alter during aging and malignant transformation. Indeed, selenoproteins possess unique properties and function with tissue-specific expression patterns and nonredundant or redundant functions across different hematopoietic lineages. Understanding the contribution of selenoproteins to hematopoietic regulation offers promising avenues for developing targeted therapeutic strategies in hematologic disorders and rejuvenating aged hematopoiesis, potentially through precision-guided modulation of selenoprotein-dependent pathways.

硒蛋白是一类独特的抗氧化酶，其催化核心是硒半胱氨酸的结合，在造血过程中作为氧化还原稳态的关键调节因子。这篇综述阐明了硒蛋白介导的氧化还原控制如何协调造血干细胞（HSC）的命运决定，维持自我更新和分化之间的关键平衡。谷胱甘肽过氧化物酶（GPX）家族，特别是GPX1和GPX4，分别在过氧化氢解毒和保护脂质过氧化诱导的铁致细胞死亡中发挥着不可或缺的作用。类似地，硫氧还蛋白还原酶（TXNRDs）通过硫氧还蛋白再生维持临界氧化还原平衡。最近的研究表明，这些氧化还原调节剂促进造血干细胞和成熟谱系的增殖和分化。硒蛋白缺乏会破坏HSC的适应性，损害B和红系的成熟，并诱导B到髓系的转换——在老年造血中观察到的致病特征，突出了硒蛋白在平衡、健康的造血中的关键作用。新出现的证据表明，白血病细胞也利用硒蛋白途径来减轻氧化应激，这表明选择性调节特定的硒蛋白可能是一种很有前途的治疗方法，前提是我们描述了正常和恶性造血之间硒蛋白的不同利用。硒蛋白在几个转录网络的交叉点起作用，包括NRF2，其精心安排的抗氧化反应可能在衰老和恶性转化过程中发生改变。事实上，硒蛋白具有独特的性质和功能，具有组织特异性表达模式和在不同造血谱系中的非冗余或冗余功能。了解硒蛋白对造血调节的贡献，为开发针对血液系统疾病的靶向治疗策略和恢复老年造血提供了有希望的途径，可能通过精确引导硒蛋白依赖途径的调节。

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引用次数: 0

Integrin-dependence of extramedullary erythropoiesis in the spleen of Jak2-V617F positive myeloproliferative neoplasm in mice 小鼠Jak2-V617F阳性骨髓增殖性肿瘤脾脏中整合素依赖性的髓外红细胞生成。

IF 2.1 4区医学 Q2 HEMATOLOGY

Experimental hematology

Pub Date : 2025-12-06 DOI: 10.1016/j.exphem.2025.105340

Conny K. Baldauf , Linda Poschmann , Bärbel Edelmann-Stephan , Frank Angenstein , Tobias R. Haage , Vikas Bhuria , Lars Philipsen , Hannes Berlin , Daniela C. Dieterich , Martin Böttcher , Dimitrios Mougiakakos , Burkhart Schraven , Thomas Fischer

The molecular mechanisms driving splenomegaly in myeloproliferative neoplasms (MPNs) remain poorly understood. Utilizing the Jak2-V617F knock-in mouse model, we investigated the role of β1- and β2-integrins in regulating spleen volume and spleen weight. The response to neutralizing antibodies against VLA-4 and the β2-integrin chain, as well as to isotype controls, was evaluated by serial intraindividual magnetic resonance imaging, by assessment of spleen weight and by analysis of the cellular composition of spleens. Short-term anti-VLA-4/β2-integrin treatment (applied on day 1 and evaluated at day 8) significantly reduced the spleen volume by 30% compared with the immunoglobulin G (IgG) control. At the cellular level, anti-integrin treatment led to a substantial 30% decrease in erythroblast counts and a 23% reduction in basophilic erythroblasts within the spleen, as compared with the isotype control. Furthermore, immunohistochemistry analysis of spleen sections revealed that CD71 (= Transferrin receptor protein 1) expression in spleen remained largely unchanged, whereas there was a clear reduction in Ter119 expression upon anti-integrin treatment. These data suggest that the substantial decrease in erythroblasts following anti-integrin treatment is a primary factor contributing to the overall reduction in spleen size. To study the spleen architecture, multiepitope ligand cartography (MELC) analysis of spleen sections was applied. This demonstrated that the spatial distribution of the marginal zone, red pulp, and white pulp remained unaltered upon anti-integrin treatment in JAK2-V617F knock-in mice. In summary, the present study identified a previously unrecognized role of the β1-integrin VLA-4 and of β2-integrin chains in extramedullary erythropoiesis of the spleen in JAK2-V617F-induced disease.

骨髓增生性肿瘤（MPN）脾肿大的分子机制尚不清楚。利用Jak2-V617F敲入小鼠模型，我们研究了β1和β2整合素在调节脾脏体积和脾脏重量中的作用。通过连续的个体内MRI、脾脏重量评估和脾脏细胞组成分析来评估抗VLA-4和β2整合素链中和抗体以及同型对照的反应。短期抗vla4 /β2整合素治疗（第1天应用，第8天评估）与IgG对照组相比，脾脏体积显著减少30%。在细胞水平上，与同型对照相比，抗整合素治疗导致脾脏内红细胞计数显著减少30%，嗜碱性红细胞减少23%。此外，脾脏切片的免疫组化分析显示，CD71（=转铁蛋白受体蛋白1）在脾脏中的表达基本保持不变，而抗整合素治疗后Ter119的表达明显降低。这一数据表明，抗整合素治疗后红细胞的大量减少是导致脾脏大小总体缩小的主要因素。为了研究脾脏的结构，应用了脾脏切片的多表位配体图谱（MELC）分析。这表明JAK2-V617F敲入小鼠的边缘区、红髓和白髓的空间分布在抗整合素处理后保持不变。总之，本研究确定了β1-整合素VLA-4和β2-整合素链在jak2 - v617f诱导的疾病中脾髓外红细胞生成中先前未被认识到的作用。

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引用次数: 0

Tumor necrosis factor from leukemic environment stimulates hematopoietic stem/progenitor cells toward megakaryocyte/myeloid lineage bias 来自白血病环境的肿瘤坏死因子刺激造血干细胞/祖细胞向巨核细胞/髓细胞谱系倾斜。

IF 2.1 4区医学 Q2 HEMATOLOGY

Experimental hematology

Pub Date : 2025-12-04 DOI: 10.1016/j.exphem.2025.105332

Hidekazu Nishikii , Riko Kikuchi , Takaharu Kimura , Mizuki Saito , Yusuke Kiyoki , Saki Tanaka , Yamato Sasaki , Takayasu Kato , Tatsuhiro Sakamoto , Mamiko Sakata-Yanagimoto , Naoshi Obara , Satoshi Yamazaki , Shigeru Chiba

Acute myeloid leukemia (AML) is characterized by the proliferation of malignant myeloid progenitor cells and impairment of hematopoiesis. Although genetic abnormalities within leukemic cells have been investigated in detail, definitive explanations for the damage to the normal hematopoietic system are lacking. Here, we investigated the mechanisms underlying the impairment of the residual hematopoietic system in the bone marrow in AML. We evaluated the function of residual nonleukemic (nl)-hematopoietic stem/progenitor cells (HSPCs) from the bone marrow of mice with MLL-AF9-induced AML. The nl-HSPCs in the leukemic marrow showed a megakaryocyte (MgK) and myeloid-biased gene expression signature, with enrichment of tumor necrosis factor (TNF) signaling and reduced repopulation ability. To investigate whether the upregulation of TNF signaling causes the MgK/myeloid lineage bias, we investigated the effects of TNF-α in normal hematopoietic stem cells (HSCs)/HSPCs under ex vivo expansion condition. Single-cell transcriptome analysis of these cells revealed an increased frequency of cells expressing genes related to the MgK lineage and decreased repopulation capacity compared with those of ex vivo expanded HSCs/HSPCs without TNF-α. Our data suggest that increased TNF-α in the leukemic bone marrow environment at least in part drives HSPCs toward MgK/myeloid differentiation, resulting in the exhaustion of residual normal HSCs/HSPCs. These findings offer valuable insights into leukemic biology and normal hematopoiesis.

急性髓系白血病（AML）的特点是恶性髓系祖细胞增殖和造血功能受损。虽然对白血病细胞内的遗传异常进行了详细的研究，但对正常造血系统的损害还缺乏明确的解释。在这里，我们研究了AML患者骨髓中残余造血系统受损的机制。我们评估了mll - af9诱导的AML小鼠骨髓中残留的非白血病(nl)-造血干细胞/祖细胞（HSPC）的功能。白血病骨髓中的nl-HSPC表现出巨核细胞（MgK）和骨髓偏倚基因表达特征，TNF信号富集，再生能力降低。为了研究TNF信号的上调是否会导致MgK /髓系偏倚，我们在离体扩增条件下研究了TNF-α对正常造血干细胞(HSC) / HSPC的影响。这些细胞的单细胞转录组分析显示，与没有TNF-α的体外扩增HSC / HSPC相比，表达MgK谱系相关基因的细胞频率增加，再生能力下降。我们的数据表明，白血病骨髓环境中TNF-α的增加至少在一定程度上推动了HSPC向MgK /髓样分化，导致剩余的正常HSC / HSPC耗尽。这些发现为白血病生物学和正常造血提供了有价值的见解。

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引用次数: 0

Pig and human adult hematopoietic stem and progenitor cells are overall transcriptionally similar 猪和人成人造血干细胞和祖细胞在转录上总体上是相似的。

IF 2.1 4区医学 Q2 HEMATOLOGY

Experimental hematology

Pub Date : 2025-12-01 DOI: 10.1016/j.exphem.2025.105334

Emma Bailey , Foteini Kalampalika , Raúl Sánchez-Lanzas , Justin Barclay , Amanda Jiménez-Pompa , Jun Wang , Miguel Ganuza

Over the recent years, pigs have re-emerged as an alternative source of organs for xenotransplantation into humans with the promise to overcome a worldwide shortage of human donors. Xenotransplantation still faces critical issues with immune rejection that could be potentially solved by the generation of lymphohematopoietic chimeras. Moreover, pig hematopoietic stem and progenitor cells (HSPCs) can constitute an unlimited source of HSPCs for lifesaving HSPC transplantation in bone marrow (BM) failure and after chemotherapy, among other cell therapies. The generation of these hematopoietic chimeras requires a profound study of pig hematopoiesis including pig HSPCs. Importantly, through single-cell RNA sequencing of pig BM cells we identified pig HSPC populations transcriptionally similar to those in humans and many common transcriptional regulators of hematopoiesis evolutionarily preserved in erythromyeloid and lymphoid differentiation. This supports that hematopoiesis in pigs is hierarchically organized and regulated in a very similar fashion as in humans. We also provided a sorting strategy for the identification and isolation of several putative pig HSPC populations, which should open a new means to functionally study pig hematopoiesis.

近年来，猪再次成为异种人体器官移植的替代来源，有望克服全球范围内人类供体短缺的问题。异种移植仍然面临着免疫排斥的关键问题，这可能通过产生淋巴造血嵌合体来解决。此外，猪造血干细胞和祖细胞（HSPCs）可以作为造血干细胞的无限来源，用于骨髓衰竭和化疗后的造血干细胞移植，以及其他细胞疗法。这些造血嵌合体的产生需要对猪造血包括猪造血干细胞和祖细胞（HSPCs）进行深入的研究。重要的是，通过对猪骨髓细胞的单细胞RNA测序，我们发现猪HSPC群体在转录上与人类相似，并且在红细胞和淋巴细胞分化中进化地保留了许多常见的造血转录调节因子。这支持了猪的造血系统以与人类非常相似的方式分层组织和调节。我们还提供了一种分类策略，用于鉴定和分离几个假定的猪HSPC群体，这将为功能性研究猪造血开辟新的手段。

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引用次数: 0

Germline heterozygous SH2B3 p.Glu78Lys variant: a three-patient case series with myeloproliferative neoplasms 种系杂合SH2B3 p.g u78lys变异：骨髓增生性肿瘤（mpn）的3例病例系列

IF 2.1 4区医学 Q2 HEMATOLOGY

Experimental hematology

Pub Date : 2025-11-29 DOI: 10.1016/j.exphem.2025.105333

Giovanni Iaquinta , Alessandro Laganà , Anna Tamburini , Caterina Tatarelli , Patrizia Chiusolo , Elena Rossi , Monica Rossi , Michele Ragazzo , Emanuele Savino , Massimo Breccia , Paola Grammatico

We investigated the clinical significance of a rare germline SH2B3 variant (c.232G>A; p.Glu78Lys) identified by targeted next-generation sequencing (NGS) in patients with myeloproliferative neoplasms (MPNs). Among approximately 330 patients, three heterozygous carriers (≈1.0% prevalence) were identified by NGS and confirmed as germline (buccal swab) by Sanger sequencing. Two of the carriers presented with essential thrombocythemia that progressed to secondary myelofibrosis, and one presented with primary myelofibrosis that evolved to acute myeloid leukemia. The variant co-occurred with canonical somatic drivers (CALR or MPL) in the first two cases and with MPL plus additional somatic alterations (SRSF2, TET2) in the third. The p.Glu78Lys substitution localizes in the N-terminal dimerization domain of SH2B3. This germline variant is rare in population databases (allele frequency ∼1.1–2.2 per 1,000 inhabitants), and is currently classified as a variant of uncertain significance. In silico predictions were discordant, whereas structural modeling predicts disruption of critical hydrogen bonding at the dimer interface, suggesting potential functional impact. Although heterozygosity alone appears insufficient to drive disease, the enrichment of this variant in our MPN cohort and its occurrence in relatively young patients support a possible low-penetrance predisposition role. Functional assays, larger case–control series, and assessment of genetic/epigenetic modifiers are needed to define pathogenicity and clinical utility.

背景：我们研究了一种罕见的种系SH2B3变异（c.232G> a; p.Glu78Lys）在骨髓增殖性肿瘤（mpn）患者中通过靶向下一代测序（NGS）鉴定的临床意义。方法：在330例患者中，通过NGS鉴定出3例杂合携带者（患病率≈1.0%），通过Sanger测序（SS）确认为种系（口腔拭子）。结果：两名携带者表现为原发性血小板增多症（ET），发展为继发性骨髓纤维化（SMF），一名携带者表现为原发性骨髓纤维化（PMF），发展为急性髓性白血病（AML）。该变异在前两例中与典型体细胞驱动因子（CALR或MPL）共同发生，在第三例中与MPL加额外的体细胞改变（SRSF2, TET2）共同发生。p.Glu78Lys取代定位于SH2B3的n端二聚化结构域（DD）。这种种系变异在种群数据库中是罕见的（等位基因频率为每1000名居民1.1-2.2），目前被归类为不确定意义变异（VUS）。在计算机上的预测是不一致的，而结构模型预测在二聚体界面的关键氢键的破坏，表明潜在的功能影响。结论：虽然杂合性本身不足以驱动疾病，但该变异在我们的MPN队列中的富集及其在相对年轻的患者中的发生支持了可能的低外显率易感性作用。需要功能测定、更大的病例对照系列和遗传/表观遗传修饰因子的评估来确定致病性和临床应用。摘要：我们在3例骨髓增殖性肿瘤患者中报道了一种罕见的杂合种系SH2B3 （c.232G> a; p.Glu78Lys）。结构模型表明，该变体的SH2B3二聚体被破坏，这可能具有潜在的功能影响。虽然杂合性本身似乎不足以驱动疾病，但我们认为SH2B3 p.g u78lys变异可能决定了一种可能的低外显率易感性，需要功能验证和更广泛的筛选。

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