Experimental hematology最新文献_第2页

Optimal ex vivo production of functional neutrophils is dependent on the source of CD34+ human hematopoietic progenitors 体外功能中性粒细胞的最佳生产依赖于CD34+人造血祖细胞的来源。

IF 2.1 4区医学 Q2 HEMATOLOGY

Experimental hematology

Pub Date : 2026-01-01 DOI: 10.1016/j.exphem.2025.105251

Kyle D. Timmer , Daniel J. Floyd , Nathan E. Jeffries , Elizabeth C. Trull , Emma E. Yvanovich , Orion Furmanski , Kristin Gilchrist , George Klarmann , Shenglin Mei , Jelena Milosevic , Vincent B. Ho , David B. Sykes , Michael K. Mansour

Neutrophils serve as the first line of defense against invasive bacterial and fungal pathogens. The loss of circulating neutrophils leaves patients at a critical risk of life-threatening infections. In this study, we optimized conditions for expanding human precursor neutrophils ex vivo while preserving the functional capacity of mature neutrophils. We evaluated several CD34+ hematopoietic stem cells (HSCs) from various sources, including umbilical cord blood (UCB), adult bone marrow (BM), and cadaveric sources. UCB-derived CD34+ cells consistently demonstrated the highest expansion capacity, achieving an additional two cell divisions compared with BM-derived cells. Surface receptor profiling demonstrated that all sources resulted in mature neutrophil differentiation, although UCB-derived cell sources exhibited higher expression of maturation markers CD11b, CD15, and CD66b, in conditions expanded with the small molecule UM729. Functionally, neutrophils derived from all cell sources retained the ability to phagocytose and produce reactive oxygen species (ROS), with enhanced activity following antibody-dependent opsonization. To better understand the impact of opsonization, Fc receptor expression levels were assessed in addition to profiling changes in complement and adhesion receptor expression. Single-cell expression analysis confirmed that ex vivo differentiation was consistent with known patterns of myeloid differentiation, leading to distinct neutrophil subpopulations. Notably, mature neutrophils generated ex vivo were transcriptionally distinct from freshly isolated primary cells. Overall, our findings demonstrate that UCB-derived precursors offer the highest expansion potential for generating neutrophil precursors, able to mature into fully functional neutrophils. These results provide valuable insights into optimizing human neutrophil production as a promising cellular therapy for neutropenic individuals.

中性粒细胞是抵御侵入性细菌和真菌病原体的第一道防线。循环中性粒细胞的丧失使患者处于危及生命的感染的危险之中。在本研究中，我们优化了体外扩增人前体中性粒细胞的条件，同时保留了成熟中性粒细胞的功能。我们评估了几种来自不同来源的CD34+造血干细胞（hsc），包括脐带血（UCB）、成人骨髓（BM）和尸体来源。与bm来源的细胞相比，ucb来源的CD34+细胞始终表现出最高的扩增能力，实现了额外的两次细胞分裂。表面受体谱分析表明，所有来源都导致成熟中性粒细胞分化，尽管ucb来源的细胞来源在小分子UM729扩增的条件下表现出更高的成熟标记CD11b、CD15和CD66b的表达。在功能上，来自所有细胞来源的中性粒细胞保留了吞噬和产生活性氧（ROS）的能力，在抗体依赖性调理后活性增强。为了更好地了解调理作用的影响，除了分析补体和粘附受体表达的变化外，还评估了Fc受体的表达水平。单细胞表达分析证实，体外分化与已知的髓细胞分化模式一致，导致不同的中性粒细胞亚群。值得注意的是，体外产生的成熟中性粒细胞在转录上与新鲜分离的原代细胞不同。总的来说，我们的研究结果表明，ucb衍生的前体在生成中性粒细胞前体方面具有最高的扩增潜力，能够成熟为功能齐全的中性粒细胞。这些结果为优化人类中性粒细胞生产提供了有价值的见解，作为中性粒细胞减少个体的一种有前途的细胞疗法。脐带CD34+祖细胞最优扩增并分化为功能性人中性粒细胞。

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引用次数: 0

Analysis of risk factors for early death of lymphocyte subsets in adult patients with secondary hemophagocytic lymphohistiocytosis 成人继发性噬血细胞性淋巴组织细胞增多症患者淋巴细胞亚群早期死亡的危险因素分析。

IF 2.1 4区医学 Q2 HEMATOLOGY

Experimental hematology

Pub Date : 2026-01-01 DOI: 10.1016/j.exphem.2025.105286

Xiaosui Ling , Heng Chen , Xiuqin Zhang , Tangxing Xu , Aigen Deng , Jing Yang

Secondary hemophagocytic lymphohistiocytosis (sHLH) is a life-threatening hyperinflammatory syndrome with high early mortality. This retrospective study of 96 adult patients with sHLH aimed to identify prognostic factors for early death, with a focus on lymphocyte subsets and clinical biomarkers. Using univariate and multivariate Cox regression analyses for 30, 60, and 90-day mortality, we demonstrated that CD3⁻CD16/CD56⁺ cells <2% were a strong independent predictor of early mortality across all time points. Furthermore, CD3⁺ cells (<50%) independently predicted 60-day mortality, whereas hemoglobin concentration (<70 g/L) emerged as an independent risk factor specifically for 30-day mortality. Elevated ferritin concentration (>10,000 ng/mL) was also significantly associated with poor outcomes, consistent with established literature. Importantly, lymphoma- or Epstein-Barr virus (EBV)-associated sHLH remained an independent predictor of early mortality after multivariate adjustment. These findings indicate that reduced CD3⁻CD16/CD56⁺ cells, combined with CD3⁺ cell depletion, anemia, and hyperferritinemia, provide valuable prognostic information for risk stratification and targeted therapeutic interventions to reduce early mortality in patients with sHLH.

继发性噬血细胞性淋巴组织细胞增多症（sHLH）是一种危及生命的高炎性综合征，具有很高的早期死亡率。本研究对96例sHLH成人患者进行回顾性研究，旨在确定早期死亡的预后因素，重点关注淋巴细胞亚群和临床生物标志物。通过对30天、60天和90天死亡率的单因素和多因素Cox回归分析，我们发现CD3⁻CD16/CD56 +细胞10000 ng/mL也与不良预后显著相关，与已有文献一致。重要的是，在多变量调整后，淋巴瘤或ebv相关sHLH仍然是早期死亡率的独立预测因子。这些发现表明，CD3⁻CD16/CD56 +细胞减少，结合CD3 +细胞耗尽、贫血和高铁蛋白血症，为风险分层和有针对性的治疗干预提供了有价值的预后信息，以降低sHLH患者的早期死亡率。摘要：继发性噬血细胞性淋巴组织细胞增多症（sHLH）是一种危及生命的高炎性综合征，具有很高的早期死亡率。关键的血液指标能预测谁的风险最大吗？一项新的研究发现CD3⁻CD16/CD56⁺的细胞减少、CD3⁺的细胞消耗、低血红蛋白、高铁蛋白和淋巴瘤/EBV关联是关键信号，为指导更早、更有针对性的治疗和减少死亡提供了线索。

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引用次数: 0

Anti-IL-18 immunotherapy decreases inflammatory and vaso-occlusive responses in mice with sickle cell disease 抗il -18免疫疗法可降低镰状细胞病小鼠的炎症和血管闭塞反应。

IF 2.1 4区医学 Q2 HEMATOLOGY

Experimental hematology

Pub Date : 2025-12-31 DOI: 10.1016/j.exphem.2025.105366

Érica M.F. Gotardo , Lidiane S. Torres , Irmgard Förster , Lucas F.S. Gushiken , Pâmela L. Brito , Flavia C. Leonardo , Bruna Cunha Zaidan , Andreas Bruederle , Sergei Agoulnik , Jiri Kovarik , John Millholland , Fernando F. Costa , Nicola Conran

Sickle cell disease (SCD) is characterized by inflammatory and vaso-occlusive processes that drive acute crises and progressive organ damage. Interleukin-18 (IL-18), elevated in patients with SCD and mouse models, contributes to these pathological mechanisms. We evaluated the effects of acute and prolonged IL-18 blockade using the SK113AE-4 monoclonal antibody in Townes and Berkeley SCD mice. Acute IL-18 neutralization reduced tumor necrosis factor-alpha (TNF-α)-induced microvascular leukocyte recruitment and prevented hypoperfusion, indicating that modulation of inflammatory signaling improves physiological responses in SCD. Prolonged anti-IL-18 immunotherapy for 6 weeks decreased circulating TNF-α and IL-10 and reduced hepatic macrophage infiltration, but did not prevent liver fibrosis, iron deposition, or alter biochemical markers of hemolysis or hepatic/renal injury. As such, IL-18 blockade attenuates vascular inflammation and vaso-occlusive-like events but may be insufficient to prevent SCD-related liver injury under the conditions tested. In contrast, in our previous study, anti-IL-1β immunotherapy provided added liver protection, highlighting potentially divergent cytokine pathways in SCD. Collectively, these results support IL-18 as a therapeutic target to reduce vascular inflammation and vaso-occlusive processes, and suggest that combined inflammasome cytokine-targeted or multiapproach strategies may be required to prevent organ damage in SCD.

背景：镰状细胞病（SCD）以炎症和血管闭塞过程为特征，可导致急性危象和进行性器官损伤。白细胞介素-18 （IL-18）在SCD患者和小鼠模型中升高，参与了这些病理机制。方法：应用SK113AE-4单克隆抗体对Townes和Berkeley SCD小鼠进行急性和长期阻断IL-18的效果评价。结果：急性IL-18中和可减少TNF-α-诱导的微血管白细胞募集，防止灌注不足，表明炎症信号的调节可改善SCD的生理反应。延长抗il -18免疫治疗6周，可降低循环TNF-α和IL-10，减少肝巨噬细胞浸润，但不能预防肝纤维化、铁沉积，也不能改变溶血或肝/肾损伤的生化指标。因此，IL-18阻断可减轻血管炎症和血管闭塞样事件，但在测试条件下可能不足以预防scd相关的肝损伤。相反，在我们之前的研究中，抗il -1β免疫治疗提供了额外的肝脏保护，突出了SCD中潜在的不同细胞因子通路。结论：总的来说，这些结果支持IL-18作为减少血管炎症和血管闭塞过程的治疗靶点，并提示可能需要联合炎性小体细胞因子靶向或多途径策略来预防SCD的器官损伤。摘要：IL-18在镰状细胞病（SCD）中升高，并参与炎症和血管闭塞途径。在两种SCD小鼠模型中，我们发现急性IL-18阻断可改善微血管反应并保留TNF-α攻击后的皮肤灌注。长期抑制IL-18可减少一些炎症标志物，但不能预防肝损伤。这些发现支持IL-18作为限制SCD血管炎症的靶点，同时表明预防器官损伤可能需要更广泛或联合的方法。

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引用次数: 0

ER-diffusion barriers exist in hematopoietic stem cell mitoses, but are not required for lysosomal asymmetric cell division. 造血干细胞有丝分裂存在内质网扩散屏障，但溶酶体不对称细胞分裂不需要内质网扩散屏障。

IF 2.1 4区医学 Q2 HEMATOLOGY

Experimental hematology

Pub Date : 2025-12-31 DOI: 10.1016/j.exphem.2025.105364

Florin Schneiter, Dirk Loeffler, Timm Schroeder

Hematopoietic stem cells (HSCs) maintain the blood system by balancing self-renewal versus mature blood cell generation. One mechanism contributing to this balance is asymmetric cell division (ACD), which relies on tightly regulated intracellular compartmentalization. In other cell types, endoplasmic reticulum diffusion barriers (ER-DBs) contribute to the targeted distribution of cellular components and cell fate regulators during ACDs. Here, we identified ER-DBs as a feature of a subset of HSC divisions. Using fluorescence recovery after photobleaching (FRAP) and time-lapse confocal microscopy, we observe ER-DBs in around 30% of mitotic HSCs. These ER-DBs are significantly weakened by fingolimod, a potent inhibitor of sphingosine-1-phosphate receptor and ceramide synthesis, implicating sphingolipid metabolism in their regulation. We found that strong ER-DBs are not required for the asymmetric inheritance of lysosomes during HSC ACD. This demonstrates that ER-diffusion barriers are present and regulated during HSC division and are an additional mechanism orchestrating molecular polarization and asymmetric inheritance in HSC divisions, independently of the mechanism regulating lysosomal asymmetry.

造血干细胞（hsc）通过平衡自我更新和成熟血细胞的生成来维持血液系统。促成这种平衡的一种机制是不对称细胞分裂（ACD），它依赖于严格调节的细胞内区隔化。在其他细胞类型中，内质网扩散屏障（er - db）有助于ACDs期间细胞成分和细胞命运调节因子的靶向分布。在这里，我们确定er - db作为HSC分裂的一个子集的特征。利用光漂白后荧光恢复（FRAP）和延时共聚焦显微镜，我们在大约30%的有丝分裂hsc中观察到er - db。这些er - db被芬戈莫德（一种有效的鞘鞘醇-1-磷酸受体和神经酰胺合成抑制剂）显著削弱，暗示鞘脂代谢参与了它们的调节。我们发现，在HSC ACD中，溶酶体的不对称遗传并不需要强er - db。这表明内质网扩散屏障在HSC分裂过程中存在并受到调节，并且是HSC分裂中协调分子极化和不对称遗传的另一种机制，独立于调节溶酶体不对称的机制。摘要：内质扩散屏障（er - db）在细胞分裂过程中控制着细胞命运调节因子的分布，也有助于细胞不对称分裂（ACD）。在这里，我们证明er - db也存在于HSC分裂的一个子集中，并且它们的强度取决于鞘脂代谢。虽然它们不是HSC溶酶体不对称细胞分裂所必需的，但这些障碍是HSC分裂中协调极化和不对称遗传的额外机制。

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引用次数: 0

Laminin receptor characterization in acute myeloid leukemia: integrin α7β1 defines leukemic cells with migratory potential 急性髓系白血病层粘连蛋白受体特征：整合素α7β1决定白血病细胞的迁移潜能。

IF 2.1 4区医学 Q2 HEMATOLOGY

Experimental hematology

Pub Date : 2025-12-25 DOI: 10.1016/j.exphem.2025.105363

Elsa Görsch , Saskia Simone Rudat , Marlon Arnone , Hildegard Keppeler , Nandini Asokan , Jan C. Schröder , Taylor Scott Mills , Lucas Mix , Lea Kramer , Jan Pauluschke-Fröhlich , Maksim Klimiankou , Jan Weller , Gerd Klein , Claudia Lengerke

Interactions with the bone marrow (BM) niche are crucial for promoting self-renewal and survival of acute myeloid leukemia (AML) cells. Consequently, AML cells express a variety of surface receptors to engage with BM niche cells and extracellular matrix proteins, including laminins. Despite the association of laminin receptors with stemness in healthy hematopoiesis, their role in AML remains poorly understood. In this study, we present a comprehensive examination of the laminin receptors integrin α3β1, α6β1, α7β1, and basal cell adhesion molecule (BCAM) in AML. We demonstrate that high messenger RNA (mRNA) expression of all four laminin receptors correlates with poor overall survival. Notably, integrin α6 (ITGA6) and integrin α7 (ITGA7) display the highest cell surface density among the examined laminin receptors and are more highly expressed on AML cells compared with healthy controls. Moreover, our results indicate that the absence of ITGA7 expression can identify cells with increased colony-forming potential, even in patients who are negative for the stem cell marker CD34, usually used to enrich leukemic stem cells (LSCs). Reanalyzing survival data from The Cancer Genome Atlas (TCGA)-AML cohort, ITGA7 expression further allows refinement of the risk stratification based on the LSC score, where low LSC and ITGA7 levels confer superior survival. Lastly, ITGA7 appears to mark leukemic cells with enhanced migratory potential, which can be inhibited by the anti-ITGA7 blocking antibody in vitro and in vivo. Together, our results confirm the association of high laminin receptor expression with poor prognosis and ITGA7 as a marker of high migratory leukemic cells.

与骨髓（BM）生态位的相互作用对于促进急性髓性白血病（AML）细胞的自我更新和存活至关重要。因此，AML细胞表达多种表面受体，与BM壁龛细胞和细胞外基质蛋白（包括层粘连蛋白）结合。尽管在健康的造血过程中层粘连蛋白受体与干细胞性相关，但它们在AML中的作用仍然知之甚少。在本研究中，我们全面研究了层粘连蛋白受体整合素α3β1、α6β1、α7β1和基底细胞粘附分子（BCAM）在AML中的作用。我们证明所有四种层粘连蛋白受体的高mRNA表达与较差的总生存率相关。值得注意的是，在检查的层粘连蛋白受体中，整合素α6和α7显示出最高的细胞表面密度，并且与健康对照相比，在AML细胞中表达更高。此外，我们的研究结果表明，整合素α7表达缺失可以识别集落形成潜力增加的细胞，即使在通常用于丰富LSC的干细胞标志物CD34呈阴性的患者中也是如此。重新分析来自TCGA-AML队列的生存数据，整合素α7的表达进一步细化了基于LSC评分的风险分层，其中低LSC和整合素α7水平赋予更高的生存率。最后，整合素α7似乎标志着白血病细胞具有增强的迁移潜力，抗整合素α7阻断抗体可以在体外和体内抑制这种迁移潜力。综上所述，我们的研究结果证实了层粘连蛋白受体的高表达与不良预后的关联，并确立了整合素α7作为高迁移白血病细胞的标志物。摘要：急性髓性白血病（AML）细胞通过表面受体与支持性骨髓生态位细胞和细胞外基质（ECM）蛋白相互作用。本研究表明，层粘连蛋白受体整合素α3β1、α6β1、α7β1和BCAM的高mRNA表达与较差的总生存率相关。此外，整合素α7的表达标志着白血病细胞表现出增强的迁移潜能。总之，我们相信我们的研究显著推进了我们对AML- ecm相互作用的理解，并提供了重要的见解，可能有助于开发未来治疗AML耐药的疗法。

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引用次数: 0

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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