Experimental hematology最新文献

CBX7 inhibitors affect H3K9 methyltransferase-regulated gene repression in leukemic cells CBX7抑制剂影响白血病细胞中H3K9甲基转移酶调节的基因抑制。

IF 2.5 4区医学

Experimental hematology Pub Date : 2025-02-01 DOI: 10.1016/j.exphem.2024.104691

Anne P. de Groot , Huong Nguyen , Jacobine S. Pouw , Ellen Weersing , Albertina Dethmers-Ausema , Gerald de Haan

{"title":"CBX7 inhibitors affect H3K9 methyltransferase-regulated gene repression in leukemic cells","authors":"Anne P. de Groot , Huong Nguyen , Jacobine S. Pouw , Ellen Weersing , Albertina Dethmers-Ausema , Gerald de Haan","doi":"10.1016/j.exphem.2024.104691","DOIUrl":"10.1016/j.exphem.2024.104691","url":null,"abstract":"<div><div>The epigenome of leukemic cells is dysregulated, and genes required for cell cycle arrest and differentiation may become repressed, which contributes to the accumulation of undifferentiated malignant blood cells. Here, we show that the Polycomb group protein CBX7 can interact with H3K9 methyltransferases EHMT1/2 and SETDB1. We aimed to assess whether combined interfering with these H3K9 methyltransferases and CBX7 could derepress target genes and thereby induce growth arrest of leukemic cells. We found that pharmacologic inhibition of CBX7 abolishes the interaction of CBX7 with EHMT1/2 and SETDB1 and subsequently reduces H3K9 methylation levels which reactivates target gene expression. Reversely, upon pharmacologic inhibition of H3K9 methyltransferases, CBX7 can take over gene repression. Finally, we found that combined inhibition of CBX7 and EHMT1/2 or SETDB1 had additive effects on reducing cell growth and inducing differentiation. However, we did not detect changes in epigenetic modifications, nor target gene derepression, after combination treatment. In contrast, CBX7 inhibitors alone did affect both Polycomb-associated H2Aub-mediated gene repression as well as H3K9 methyltransferase activity. Therefore, we suggest that CBX7 is a promising therapeutic target in leukemia, as its inhibition can reactivate Polycomb and H3K9 methyltransferase target gene expression.</div></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"142 ","pages":"Article 104691"},"PeriodicalIF":2.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142754804","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

KLF4 enhances transplantation-induced hematopoiesis by inhibiting TLRs and non-canonical NFκB signaling at a steady state.

IF 2.5 4区医学

Experimental hematology Pub Date : 2025-02-01 DOI: 10.1016/j.exphem.2025.104730

Chun Shik Park, Cory S Bridges, Andrew H Lewis, Taylor J Chen, Saptarsi Shai, Wa Du, Monica Puppi, Barry Zorman, Sumazin Pavel, H Daniel Lacorazza

{"title":"KLF4 enhances transplantation-induced hematopoiesis by inhibiting TLRs and non-canonical NFκB signaling at a steady state.","authors":"Chun Shik Park, Cory S Bridges, Andrew H Lewis, Taylor J Chen, Saptarsi Shai, Wa Du, Monica Puppi, Barry Zorman, Sumazin Pavel, H Daniel Lacorazza","doi":"10.1016/j.exphem.2025.104730","DOIUrl":"https://doi.org/10.1016/j.exphem.2025.104730","url":null,"abstract":"<p><p>The transcription factor Krüppel-like factor 4 (KLF4) acts as a transcriptional activator and repressor. KLF4 plays a role in various cellular processes, including the dedifferentiation of somatic cells into induced pluripotent stem cells. Although it has been shown to enhance self-renewal in embryonic and leukemia stem cells, its role in adult hematopoietic stem cells (HSC) remains underexplored. We demonstrate that conditional deletion of the Klf4 gene in hematopoietic cells led to an increased frequency of immunophenotypic hematopoietic stem cells (HSCs) in the bone marrow, along with a normal distribution of lymphoid and myeloid progenitor cells. Non-competitive bone marrow transplants showed normal engraftment and multi-lineage reconstitution, except for monocytes and T cells. However, the loss of KLF4 hindered hematological reconstitution in competitive serial bone marrow transplants, highlighting a critical role for KLF4 in stress-induced hematopoiesis. Transcriptome analysis revealed an upregulation of NFκB2 and toll-like receptors (e.g., TLR4) in Klf4-null HSCs during homeostasis. Flow cytometry and immunoblot analysis confirmed the increased cell surface expression of TLR4 and the activation of NFκB2 in HSCs under homeostatic conditions, whereas NFκB2 expression drops after radiation compared to steady-state levels. Our findings suggest that the constitutive activation of the TLR4-NFκB2 pathway inhibits the ability of HSCs to regenerate blood after transplantation in cytoablated bone marrow.</p>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":" ","pages":"104730"},"PeriodicalIF":2.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143122536","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Nucleic acid metabolism: the key therapeutic target for myeloid tumors 核酸代谢：髓系肿瘤的关键治疗靶点。

IF 2.5 4区医学

Experimental hematology Pub Date : 2025-02-01 DOI: 10.1016/j.exphem.2024.104693

Tomohiro Yabushita , Susumu Goyama

引用次数: 0

Sex-stratified association of variants in the serotonin 1A receptor gene with acute crisis pain among African American patients with sickle cell disease 5 -羟色胺1A受体基因变异与非裔美国人镰状细胞病患者急性危重性疼痛的性别分层关联

IF 2.5 4区医学

Experimental hematology Pub Date : 2025-02-01 DOI: 10.1016/j.exphem.2024.104692

Nilanjana Sadhu , Ying He , Yavnika Kashyap , Giokdjen Ilktach , Michael A. Wang , Yingwei Yao , Diana J. Wilkie , Robert E. Molokie , Zaijie Jim Wang

{"title":"Sex-stratified association of variants in the serotonin 1A receptor gene with acute crisis pain among African American patients with sickle cell disease","authors":"Nilanjana Sadhu , Ying He , Yavnika Kashyap , Giokdjen Ilktach , Michael A. Wang , Yingwei Yao , Diana J. Wilkie , Robert E. Molokie , Zaijie Jim Wang","doi":"10.1016/j.exphem.2024.104692","DOIUrl":"10.1016/j.exphem.2024.104692","url":null,"abstract":"<div><div>Patients with sickle cell disease (SCD) experience pain in their daily lives. Both the acute and chronic pain phenotypes of this disease exhibit high variability, making pain management a challenge. The underlying reasons for the phenotypic variability are poorly understood. Given the importance of serotonergic neurotransmission in pain signaling, we aimed to explore the role of variants in the 5-HT1A receptor gene (<em>HTR1A</em>) on pain variability in SCD. Four variants (rs6449693, rs878567, rs6294, and rs10042486) in <em>HTR1A</em> were genotyped in a cohort of 131 African Americans with SCD. Acute and chronic pain were measured by the acute care utilization and the McGill Pain Questionnaire, respectively. Association analyses were performed for three genetic models (additive, dominant, and recessive). Three variants (rs6449693, rs6294, and rs10042486) in <em>HTR1A</em> showed significant association with crisis pain in both the additive and dominant models. Although the G allele of rs6449693 and the C allele of rs10042486 associated with lower acute crisis pain, the T allele of rs6294 associated with increased acute crisis pain. Sex-stratified analyses revealed that the associations of these three variants with acute pain were significant only in men, but not in women. Furthermore, the A allele rs878567 that did not reach statistical significance in the overall cohort showed a significant association with lower crisis pain in men. To our knowledge, as the first study to explore the role of <em>HTR1A</em> variants in sickle cell pain, we identified that four variants across the gene are associated with acute crisis pain in SCD in a sex-stratified manner.</div></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"142 ","pages":"Article 104692"},"PeriodicalIF":2.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142767462","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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The developmental clock: where art and science meet 发育时钟：艺术与科学交汇的地方。

IF 2.5 4区医学

Experimental hematology Pub Date : 2025-02-01 DOI: 10.1016/j.exphem.2024.104695

John D. Crispino

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Novel techniques to quantitatively assess age-dependent alterations in biophysical properties of HSPCs and bone marrow niche 定量评估HSPCs和骨髓生态位生物物理特性随年龄变化的新技术。

IF 2.5 4区医学

Experimental hematology Pub Date : 2025-02-01 DOI: 10.1016/j.exphem.2024.104686

Anthony D. Ho , Motomu Tanaka

{"title":"Novel techniques to quantitatively assess age-dependent alterations in biophysical properties of HSPCs and bone marrow niche","authors":"Anthony D. Ho , Motomu Tanaka","doi":"10.1016/j.exphem.2024.104686","DOIUrl":"10.1016/j.exphem.2024.104686","url":null,"abstract":"<div><div>The present knowledge on hematopoietic stem and progenitor cell (HSPC) biology and aging is based largely on studies in mouse models. Although mouse models are invaluable, they are not without limitations for defining how physical properties of HSPCs and their niche change with age. The bone marrow (BM) niche is a complex, interactive environment with multiple cell types. The structure and organization of the BM niche, especially the extracellular matrix (ECM), change with age. Provided with recent advances in quantitative analytical techniques and in vitro niche models, we have developed novel tools to quantitatively assess the impact of specific biochemical and physical cues on homing, adhesion, and migration of HSPCs. Recent developments in in vitro niche models have also provided new insights into the interactions between HSPCs and their niche, particularly the role of matrix stiffness. Further research is needed to integrate physical biomarkers into comprehensive mathematical models of age-dependent HSPC-niche interactions. The key is to use mouse models in conjunction with direct analyses in in vitro niche models to achieve a more comprehensive understanding of age-dependent alterations in niche function and regulation.</div></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"142 ","pages":"Article 104686"},"PeriodicalIF":2.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142754825","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Chronic murine schistosomiasis causes aberrant hemostasis 摘要：慢性小鼠血吸虫病引起异常止血。

IF 2.5 4区医学

Experimental hematology Pub Date : 2025-02-01 DOI: 10.1016/j.exphem.2024.104689

Joanna H. Greenman , Lucie Moss , Shinjini Chakraborty , Bradley J. Whitehead , Johan Palmfeldt , Peter Nejsum , James P. Hewitson , Ian S. Hitchcock

{"title":"Chronic murine schistosomiasis causes aberrant hemostasis","authors":"Joanna H. Greenman , Lucie Moss , Shinjini Chakraborty , Bradley J. Whitehead , Johan Palmfeldt , Peter Nejsum , James P. Hewitson , Ian S. Hitchcock","doi":"10.1016/j.exphem.2024.104689","DOIUrl":"10.1016/j.exphem.2024.104689","url":null,"abstract":"<div><div>Schistosomiasis afflicts >250 million people worldwide, leading to an annual loss of >3 million disability-adjusted life years. <em>Schistosoma mansoni</em> causes intestinal schistosomiasis with parasite eggs either transversing intestinal tissue or lodging within the liver and other organs, causing intestinal hemorrhage and liver pathology. Large (∼1 cm) adult worms survive for years within blood vessels, but we lack a clear understanding of their impact on hemostasis. We used a chronic mouse model of schistosomiasis to determine the impact on platelet numbers, phenotype and function. Hemostatic function was assessed by platelet phenotyping (flow cytometry and proteomics), whole blood aggregometry, and longitudinal coagulometry. Although platelets from schistosome-infected mice lack elevated surface P-selectin and activated αIIbβ3, unbiased proteomic analysis reveals infection-induced increases in MHC-I, IgM and IgG antibodies, and complement components. Whole blood from schistosome-infected mice spontaneously aggregates in the absence of exogenous agonists. Conversely, prothrombin and activated partial thromboplastin times are prolonged at the chronic stage of infection (10–12 weeks). A mouse model of <em>S. mansoni</em> infection shows wide-ranging changes in hemostatic function which may have clinically relevant implications for populations in endemic regions.</div></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"142 ","pages":"Article 104689"},"PeriodicalIF":2.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142767458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

IFC Editorial Board

IF 2.5 4区医学

Experimental hematology Pub Date : 2025-02-01 DOI: 10.1016/S0301-472X(25)00006-2

引用次数: 0

Methodological Considerations on How to Identify Human Hematopoietic Stem Cells.

IF 2.5 4区医学

Experimental hematology Pub Date : 2025-01-30 DOI: 10.1016/j.exphem.2025.104729

Taylor Hinchly, Dominique Bonnet, Fernando Anjos-Afonso

引用次数: 0

TET2-loss enhances immediate and time-resolved interferon-γ signaling responses across myeloid differentiation. TET2缺失会增强整个髓系分化过程中即时和时间分辨的 IFNγ 信号反应。

IF 2.5 4区医学

Experimental hematology Pub Date : 2025-01-22 DOI: 10.1016/j.exphem.2025.104727

Matthew T Jenkins, Yunli E Chu, Alana M Franceski, Chad R Potts, Rebecca Dubin, Kirsten M Dickerson, Stanley C Lee, Rui Lu, Robert S Welner, P Brent Ferrell

{"title":"TET2-loss enhances immediate and time-resolved interferon-γ signaling responses across myeloid differentiation.","authors":"Matthew T Jenkins, Yunli E Chu, Alana M Franceski, Chad R Potts, Rebecca Dubin, Kirsten M Dickerson, Stanley C Lee, Rui Lu, Robert S Welner, P Brent Ferrell","doi":"10.1016/j.exphem.2025.104727","DOIUrl":"10.1016/j.exphem.2025.104727","url":null,"abstract":"<p><p>Signaling responses to cytokines are disrupted in clonal hematopoiesis and myeloid malignancies. To better identify specific signaling response alterations in the presence or absence of TET2, we developed a 36-parameter cytometry by time-of-flight (CyTOF) panel of both surface marker and phosphoprotein antigens in murine bone marrow (BM). We show diverse, cell-type specific inflammatory cytokine responses in healthy hematopoietic cells. We next investigated changes associated with BM cells from Tet2<sup>KO</sup> mice. High-dimensional surface marker phenotyping revealed expansion of hematopoietic stem and progenitor cells (HSPCs), committed cKIT<sup>+</sup>Ly6C<sup>+</sup> myeloid progenitors, and monocytes. Loss of TET2 function increased the magnitude of response to extracellular perturbations, including interferon (IFN)γ and H<sub>2</sub>O<sub>2</sub>. Response time courses revealed that IFNγ-mediated pSTAT1 remains elevated over time in Tet2<sup>KO</sup>. Further, IFNγ resulted in a more significant increase in major histocompatibility complex class II (MHCII) expression in Tet2<sup>KO</sup> immortalized progenitor cells than in Tet2<sup>WT</sup>. Inhibition of Janus kinase 1 and 2 (JAK1/2) with ruxolitinib significantly reduced STAT1 phosphorylation and MHCII expression in Tet2<sup>KO</sup> cells. Our results identify targetable disrupted signaling responses in Tet2<sup>KO</sup> cells.</p>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":" ","pages":"104727"},"PeriodicalIF":2.5,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143037740","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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