Journal of Leukocyte Biology最新文献

Metainflammation alters neutrophil function and migration in vivo in response to tissue injury. 间皮炎改变中性粒细胞功能和迁移在体内响应组织损伤。

IF 3.6 3区医学

Journal of Leukocyte Biology Pub Date : 2025-06-25 DOI: 10.1093/jleuko/qiaf094

Cassia Michael, Joaquin Canton Sandoval, Maria Feliz-Norberto, Pablo Scharf, Sofia de Oliveira

{"title":"Metainflammation alters neutrophil function and migration in vivo in response to tissue injury.","authors":"Cassia Michael, Joaquin Canton Sandoval, Maria Feliz-Norberto, Pablo Scharf, Sofia de Oliveira","doi":"10.1093/jleuko/qiaf094","DOIUrl":"https://doi.org/10.1093/jleuko/qiaf094","url":null,"abstract":"Overnutrition and the consumption of Western-type diets lead to chronic low-grade systemic inflammation (i.e., metainflammation) and a dysfunctional immune response. Although neutrophils are affected by metainflammation, mechanistic evidence regarding the direct effects of dietary fat exposure on neutrophil function and migration in vivo, particularly in response to injury, remains limited. Here, we investigated how metainflammation induced by a high-cholesterol diet (HCD) influences neutrophil function and migration following tissue injury. We employed a tailfin transection model in juvenile zebrafish larvae with fluorescently tagged neutrophils fed an HCD and assessed neutrophil function and migration dynamics in vivo at the injury site and whole animal. We combined long-term, non-invasive intravital confocal microscopy with computational analysis to examine neutrophil behavior, and photoconversion techniques were used to track neutrophil mobilization across the larvae. Exposure to HCD resulted in a dysfunctional neutrophil response characterized by exacerbated recruitment, increased ROS production and NETosis, impaired apoptosis, and delayed inflammation resolution. Neutrophil forward and reverse migration were also significantly impacted at the injury site. Moreover, we identified diet-inflamed regions such as the liver and intestine as sources of activated neutrophils that reverse-migrate and respond to injuries at distant sites, contributing to inter-organ transmission of inflammation. Finally, ameliorating steatosis and systemic chronic inflammation rescued the exaggerated neutrophil recruitment to injury. Overall, our study highlights the crucial role of neutrophil dysregulation and reverse migration from diet-induced inflamed tissues in driving exaggerated and dysfunctional inflammatory responses to injury, providing insight into potential therapeutic strategies to alleviate these effects in metabolic disease.","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144484754","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Caging Giants: Characterizing the molecular mechanisms of neutrophil swarming against Candida albicans hyphae. 笼巨人：中性粒细胞聚集对抗白色念珠菌菌丝的分子机制。

IF 3.6 3区医学

Journal of Leukocyte Biology Pub Date : 2025-06-06 DOI: 10.1093/jleuko/qiaf082

Tasha K Phillips, Kelsey Lawson, Tammy R Ozment, Allison Scherer, Alex Hopke

{"title":"Caging Giants: Characterizing the molecular mechanisms of neutrophil swarming against Candida albicans hyphae.","authors":"Tasha K Phillips, Kelsey Lawson, Tammy R Ozment, Allison Scherer, Alex Hopke","doi":"10.1093/jleuko/qiaf082","DOIUrl":"https://doi.org/10.1093/jleuko/qiaf082","url":null,"abstract":"Neutrophils utilize many mechanisms to restrict fungal growth. When phagocytosis occurs, neutrophils can create many toxic antimicrobials including reactive oxygen species and the products of myeloperoxidase (MPO). If a pathogen is too large to phagocytose, neutrophils can also resort to the release of neutrophil extracellular traps (NETs) or it can engage in the behavior of \"swarming\", where the recruitment and antimicrobial action of many neutrophils are coordinated against a single target. Here we optimized an assay to study the behavior of swarming directly against live C. albicans hyphae. We find that hyphae are highly potent targets for inducing swarming behavior and that swarming is very effective at restricting hyphal growth. We provide insight into the initial interactions between the pioneer neutrophil and the hyphae, including information on how fast signaling is initiated following neutrophil binding, how far neutrophils stretch before signaling occurs, and how the calcium signaling waves are unique in response to hyphal targets. We also find distinct and important roles for MPO, spleen tyrosine kinase (SYK), Bruton's tyrosine Kinase (BTK) and CD18 in an effective neutrophil swarming response.","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144234355","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Granulocyte function in response to acute alcohol consumption: temporal shifts from proinflammatory activation to antiinflammatory modulation in healthy volunteers. 粒细胞功能对急性饮酒的反应：健康志愿者从促炎激活到抗炎调节的时间转变

IF 3.6 3区医学

Journal of Leukocyte Biology Pub Date : 2025-06-04 DOI: 10.1093/jleuko/qiaf081

Ramona Sturm, Florian Haag, Helen Rinderknecht, Jasmin Maria Bülow, Nils Wagner, Julian Zabel, Christian B Bergmann, Ingo Marzi, Borna Relja

{"title":"Granulocyte function in response to acute alcohol consumption: temporal shifts from proinflammatory activation to antiinflammatory modulation in healthy volunteers.","authors":"Ramona Sturm, Florian Haag, Helen Rinderknecht, Jasmin Maria Bülow, Nils Wagner, Julian Zabel, Christian B Bergmann, Ingo Marzi, Borna Relja","doi":"10.1093/jleuko/qiaf081","DOIUrl":"10.1093/jleuko/qiaf081","url":null,"abstract":"While chronic alcohol use is proinflammatory, the immune effects of acute intake remain unclear. We examined granulocyte responses to binge drinking, common in youth. Twenty-two volunteers consumed 12 alcoholic drinks over 4 h (blood alcohol concentration 1.0‰). Blood was collected at baseline (T0), 2 h (T2), 4 h (T4), 6 h (T6), 24 h (T24), and 48 h (T48) postintake. Interleukin (IL)-6 and M30 (inflammation, cell death) were analyzed by enzyme-linked immunosorbent assay; CXCL10 and MPO gene expression in polymorphonuclear leukocytes (PMNLs) by qRT-PCR; CD62L and Toll-like receptor (TLR4) on CD16+ granulocytes by flow cytometry; inflammasome activation post-LPS/ATP stimulation; and PMNL adhesion to A549 lung cells. IL-6 increased significantly at T2 to T6; M30 peaked at T4, decreasing at T24 and T48. CXCL10 and MPO increased at T2 and T4; MPO declined at T24 and T48. TLR4-positive granulocytes increased at T2 and T4. Active caspase-1 rose over 48 h, while stimulated activation declined at T4 and T24. CD62L increased at T2 before declining. PMNL adhesion decreased significantly at T24 and T48. Acute alcohol triggers early inflammation followed by immune suppression.","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144248274","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Sex differences in age-related cardiac and splenic S100A9 and NLRP3 expression. 年龄相关性心脏和脾脏S100A9和NLRP3表达的性别差异。

IF 3.6 3区医学

Journal of Leukocyte Biology Pub Date : 2025-06-04 DOI: 10.1093/jleuko/qiaf031

Kathleen Pappritz, Isabel Voss, Muhammad El-Shafeey, Sophie Van Linthout

引用次数: 0

Fever-range temperature alters continual efferocytosis mediated by mouse proinflammatory macrophages. 发热范围内的温度改变了小鼠促炎巨噬细胞介导的持续efferocysis。

IF 3.6 3区医学

Journal of Leukocyte Biology Pub Date : 2025-06-04 DOI: 10.1093/jleuko/qiaf061

Mathieu Vetter, Melissa Maraux, Francis Bonnefoy, Ludivine Dal Zuffo, Baptiste Lamarthée, Gwnenaël Rolin, Audrey Wetzel, Sylvain Perruche, Paul Peixoto, Philippe Saas

{"title":"Fever-range temperature alters continual efferocytosis mediated by mouse proinflammatory macrophages.","authors":"Mathieu Vetter, Melissa Maraux, Francis Bonnefoy, Ludivine Dal Zuffo, Baptiste Lamarthée, Gwnenaël Rolin, Audrey Wetzel, Sylvain Perruche, Paul Peixoto, Philippe Saas","doi":"10.1093/jleuko/qiaf061","DOIUrl":"10.1093/jleuko/qiaf061","url":null,"abstract":"Fever, a cardinal sign of inflammation, has been shown to modulate macrophage functions. Here, we investigate whether fever affects macrophage efferocytosis. This process is essential for the resolution of inflammation and the return to homeostasis with the reprogramming of macrophages toward a proresolving phenotype. Using primary mouse bone marrow-derived macrophages stimulated with lipopolysaccharide and interferon-γ (ie proinflammatory macrophages), we first validated that exposure to febrile temperature (39.5 °C) induced a heat shock protein response. Then, we observed that febrile temperature decreased the capacity of proinflammatory macrophages to uptake apoptotic cells. This reduced efferocytic capacity of macrophages exposed to febrile temperature resulted from a decreased capacity to interact with apoptotic cells and to internalize these dying cells. Exposure to febrile temperature reduced the cell motility of macrophages in response to apoptotic cells, as assessed by IncuCyte live-cell imaging. RNA sequencing analysis of proinflammatory macrophages exposed to febrile temperature identified an upregulation of the Adam17 gene. As this gene encodes a protease that sheds the efferocytic receptor Mer, we determined cell surface expression of Mer and quantified soluble Mer in the culture supernatants of proinflammatory macrophages exposed to febrile temperature. While febrile hyperthermia induced the Mer cleavage from the cell surface of proinflammatory macrophages, ADAM17 inhibition during exposure to febrile temperature did not restore the efferocytic capacity of proinflammatory macrophages. Thus, reduction of Mer expression induced by hyperthermia did not represent the main mechanism explaining reduced efferocytosis. Nevertheless, our work suggests that fever, by decreasing the efferocytic capacity of macrophages, maintains their proinflammatory state.","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144078570","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Interferon regulatory factor 8 induces intrinsic functional changes in mature neutrophils. 干扰素调节因子8诱导成熟中性粒细胞内在功能改变。

IF 3.6 3区医学

Journal of Leukocyte Biology Pub Date : 2025-06-04 DOI: 10.1093/jleuko/qiaf078

Laura Polmann, Janna Carina Grimm, Johannes Roth, Katarzyna Barczyk-Kahlert

{"title":"Interferon regulatory factor 8 induces intrinsic functional changes in mature neutrophils.","authors":"Laura Polmann, Janna Carina Grimm, Johannes Roth, Katarzyna Barczyk-Kahlert","doi":"10.1093/jleuko/qiaf078","DOIUrl":"10.1093/jleuko/qiaf078","url":null,"abstract":"Neutrophils are the first line of host defense. Neutrophils target invading pathogens by phagocytosis, generation of reactive oxygen species (ROS), neutrophil extracellular trap formation (NETosis), and cytokine production. Interferon regulatory factor 8 (IRF8) plays a central role in the regulation of myeloid cells fate, promoting monocyte and dendritic cell development while inhibiting neutrophil production. The global IRF8 deficiency leads to an accumulation of immature myeloid cells, mostly neutrophils, while IRF8 deficiency restricted to myeloid cells has no effect on myeloid cell differentiation. However, the role of IRF8 in regulating neutrophil function remains to be fully elucidated, especially due to the fact that IRF8 is not expressed in mature neutrophils. This study aims to investigate the impact of IRF8 on effector functions of neutrophils. The absence of IRF8 resulted in a diminished response of neutrophils to inflammatory challenge by lipopolysaccharide (LPS), as evidenced by reduced expression of inflammatory cytokines. This effect was intrinsic to IRF8-/- neutrophils and not driven by extrinsic factors, as assessed comparing bone marrow-derived and estrogen receptor-regulated homeobox B8-derived IRF8-/- neutrophils and was accompanied by reduced p38, extracellular signal-regulated kinase 1/2, and mitogen-activated protein kinase-activated protein kinase 2 activation. It is noteworthy that not all effector functions were affected by IRF8 deficiency. The mechanisms of pathogen elimination, such as phagocytosis and ROS production, were impaired in IRF8-/- neutrophils, whereas processes like NETosis remained entirely intact. In conclusion, our findings suggest that IRF8 shapes the neutrophil response to LPS and modulates neutrophil function, and this process is independent of external factors.","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144208646","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The release of NETs during SFTSV infection downregulates the specific inflammatory factors that lead to liver and spleen damage. SFTSV感染期间NETs的释放下调了导致肝脏和脾脏损伤的特定炎症因子。

IF 3.6 3区医学

Journal of Leukocyte Biology Pub Date : 2025-06-04 DOI: 10.1093/jleuko/qiaf053

Xuewen Ji, Xinyi Yu, Zihan Xiao, Ruonan Zhang, Zihan Wu, Xinrui Zhang, Chunhui Wang, Jin Zhu, Ye Yang, Tingting Zhou

{"title":"The release of NETs during SFTSV infection downregulates the specific inflammatory factors that lead to liver and spleen damage.","authors":"Xuewen Ji, Xinyi Yu, Zihan Xiao, Ruonan Zhang, Zihan Wu, Xinrui Zhang, Chunhui Wang, Jin Zhu, Ye Yang, Tingting Zhou","doi":"10.1093/jleuko/qiaf053","DOIUrl":"10.1093/jleuko/qiaf053","url":null,"abstract":"Severe fever with thrombocytopenia syndrome is a life-threatening condition that has been the focus of attention in recent years. It is primarily caused by uncontrolled replication of a novel Bunyavirus and an intense proinflammatory response. NETosis is a form of cell death initiated by neutrophils, involving the formation of neutrophil extracellular traps. These neutrophil extracellular traps are composed of DNA fibers or nuclear chromatin that trap cytoplasmic granule proteins and histones in a meshwork to capture and eliminate pathogens. Our investigation delved into single-cell sequencing data from patients with severe fever with thrombocytopenia syndrome, revealing that severe fever with thrombocytopenia syndrome virus can trigger NETosis in both cellular and animal models. Furthermore, we examined the impact of neutrophil extracellular traps on Thp-1 cells through transcriptome sequencing and evaluated tissues in infected animal models, unveiling a significant downregulation of specific inflammatory factors. By integrating previous research, we propose a hypothesis that the reduction of these inflammatory factors hinders the occurrence of immune responses and the process of organ repair, thereby causing tissue damage.","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143986161","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Macrophage polarization, inflammatory monocytes, and impaired MDSCs are associated with murine and human immune aplastic anemia. 巨噬细胞极化、炎性单核细胞和MDSCs受损与小鼠和人类免疫再生障碍性贫血有关。

IF 3.6 3区医学

Journal of Leukocyte Biology Pub Date : 2025-06-04 DOI: 10.1093/jleuko/qiaf073

Joshua Glass, Xingmin Feng, Jichun Chen, Jibran Durrani, Zhijie Wu, Shouguo Gao, Ruba Shalhoub, Liangliang Wu, Neal S Young

{"title":"Macrophage polarization, inflammatory monocytes, and impaired MDSCs are associated with murine and human immune aplastic anemia.","authors":"Joshua Glass, Xingmin Feng, Jichun Chen, Jibran Durrani, Zhijie Wu, Shouguo Gao, Ruba Shalhoub, Liangliang Wu, Neal S Young","doi":"10.1093/jleuko/qiaf073","DOIUrl":"10.1093/jleuko/qiaf073","url":null,"abstract":"Immune-mediated bone marrow failure (BMF) entails a complex immune landscape. Myeloid cells, including monocytes, macrophages, and myeloid-derived suppressor cells (MDSCs), are involved in the development and progression of immune aplastic anemia (AA). We used a murine model of BMF to explore the effects of CSF-1R inhibition on immune pathophysiology. Hematopoiesis, immune cell populations, and gene expression were assessed by flow cytometry, cytokine analysis, and single-cell RNA sequencing. CSF-1R inhibition with the small molecule PLX3397 intensified BMF in CByB6F1 mice, enhancing inflammation and macrophage polarization toward the proinflammatory M1 phenotype. This was accompanied by increased leukocyte apoptosis, a reduction in CD11b + myeloid cells, and worsened animal survival. In contrast, the JAK inhibitor baricitinib attenuated BMF, promoting M2 macrophage polarization, and decreasing CD8+ T cell infiltration of bone marrow. Single-cell RNA analysis revealed upregulation of M1 signature genes in both murine BMF and also AA human samples. In patients with severe AA, there was a shift toward an M1-like monocyte phenotype, correlating with increased inflammatory cytokine expression and altered MDSC populations. These findings highlight the role of myeloid-derived cells in BMF and suggest that M1 macrophages, with defective MDSC function, contribute to disease pathogenesis and progression. Targeting macrophage polarization or MDSCs offers alternative therapeutic strategies in immune-mediated BMF.","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144136193","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Nervonic acid mitigates IMQ-triggered psoriasis in mice via inhibiting Th17/γδT17 cell invasion and modulating the gut microbiota. 神经酸通过抑制Th17/γδT17细胞侵袭和调节肠道微生物群减轻imq引发的小鼠牛皮癣。

IF 3.6 3区医学

Journal of Leukocyte Biology Pub Date : 2025-06-04 DOI: 10.1093/jleuko/qiaf070

Zishan Yang, Xiaorong Geng, Shenglan Zhang, Junjie Gao, Fengxiang Ji, Yixuan Han, Zhihao Cui, Xia Wang, Sheng Guo, Dong Yan, Tiesuo Zhao, Feng Ren, Xueshi Li, Jie Dong, Zhongwei Tian, Zhinan Yin, Xiangfeng Song

{"title":"Nervonic acid mitigates IMQ-triggered psoriasis in mice via inhibiting Th17/γδT17 cell invasion and modulating the gut microbiota.","authors":"Zishan Yang, Xiaorong Geng, Shenglan Zhang, Junjie Gao, Fengxiang Ji, Yixuan Han, Zhihao Cui, Xia Wang, Sheng Guo, Dong Yan, Tiesuo Zhao, Feng Ren, Xueshi Li, Jie Dong, Zhongwei Tian, Zhinan Yin, Xiangfeng Song","doi":"10.1093/jleuko/qiaf070","DOIUrl":"10.1093/jleuko/qiaf070","url":null,"abstract":"Psoriasis is a persistent immune-mediated inflammatory dermatosis. The treatment of psoriasis now features natural medicine as an effective new alternative because of its notable effectiveness and few side effects. Nervonic acid (NA), a long-chain fatty acid mostly sourced from the seed oils of some wild plants, exhibits significant antidepressant and anti-inflammatory properties. Nonetheless, the pathogenic effects and mechanism of NA in the pathogenesis of psoriasis are unreported. This work demonstrated that NA markedly mitigated IMQ-triggered psoriasis-like skin inflammation and reduced the mRNA expression levels of chemokines (Cxcl1 and Ccl20) and inflammatory factors (S100a8, S100a9, IL-17, and IL-6) both in vitro and in vivo. Mechanistically, NA blocked the IL-17/IMQ-induced NF-κB and p38MAPK signaling pathways in keratinocytes or tissue lesions, downregulated Ccl20 production, and therefore disrupted positive inflammatory feedback by diminishing Th17 or γδT17 cell infiltration. Furthermore, 16s rRNA sequencing demonstrated that NA therapy significantly elevated the relative abundance of Bacteroidota, but the outcome for Mucispirillum was contrary within the gut microbiota. These bacteria are linked to the onset of psoriasis and inflammation, perhaps contributing to the alleviation of IMQ-induced lesions in mice. In conclusion, NA may alleviate dermatitis in psoriatic mice by inhibiting Th17/γδT17 cell invasion and modulating the gut microbiota. Consequently, NA stands as a highly promising choice for psoriasis treatment.","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144119694","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

AML1-ETO and CCND2 overexpression cooperate to drive acute myeloid leukemia initiation and progression. AML1-ETO和CCND2过表达共同驱动急性髓系白血病的发生和发展。

IF 3.6 3区医学

Journal of Leukocyte Biology Pub Date : 2025-06-04 Epub Date: 2025-05-22 DOI: 10.1093/jleuko/qiaf072

Junli Mou, Qianqian Huang, Xiaoyu Liu, Wenbing Liu, Yu Liu, Yihan Mei, Runxia Gu, Yingxi Xu, Kejing Tang, Zheng Tian, Haiyan Xing, Qing Rao, Min Wang, Shaowei Qiu, Jianxiang Wang

{"title":"AML1-ETO and CCND2 overexpression cooperate to drive acute myeloid leukemia initiation and progression.","authors":"Junli Mou, Qianqian Huang, Xiaoyu Liu, Wenbing Liu, Yu Liu, Yihan Mei, Runxia Gu, Yingxi Xu, Kejing Tang, Zheng Tian, Haiyan Xing, Qing Rao, Min Wang, Shaowei Qiu, Jianxiang Wang","doi":"10.1093/jleuko/qiaf072","DOIUrl":"10.1093/jleuko/qiaf072","url":null,"abstract":"Increasing numbers of clinical cohorts have detected CCND2 mutations in acute myeloid leukemia, especially in the subtype of acute myeloid leukemia with the t(8;21) translocation. This acute myeloid leukemia subtype is characterized by the formation of the AML1-ETO fusion gene. However, the AML1-ETO fusion gene alone is not sufficient to drive leukemia development. Additional mutations are required for leukemogenesis. In this study, we aim to investigate whether mutated CCND2 can cooperate with the AML1-ETO fusion gene to drive leukemia initiation and progression. In our previous study, the conditional AML1-ETO knock-in mouse model (AML1-ETO mouse), which represented a preleukemia stage as a myeloproliferative neoplasm phenotype, was established. To confirm whether the AML1-ETO and CCND2 mutation can cooperate to drive leukemia, the mice transduction and transplantation model harboring both AML1-ETO and CCND2 genes (both wild-type and mutant) was established. Upon the assessment of the phenotype, biological features, and survival of the mice, only the mice overexpressing AML1-ETO and CCND2 simultaneously eventually progressed to leukemia. Besides, compared to mice overexpressing the AML-ETO gene alone, mTOR and cell cycle-related pathways were significantly enriched in mice harboring both AML1-ETO and CCND2. The selective mTOR inhibitor everolimus can also reduce the leukemia burden and prolong the survival of this group of mice. In conclusion, it was confirmed that the introduction of the CCND2 gene into the AML/ETO preleukemia mice could trigger the development of leukemia. It was also confirmed that CCND2 overexpression resulted in the upregulation of the mTOR pathway, and inhibiting the pathway might be a therapeutic strategy for this subtype of leukemia.","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":"117 6","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144333275","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0