Experimental hematology最新文献

{"title":"A new anchor point for gut microbiome to regulate complications of allogeneic hematopoietic stem cell transplantation: oxidative stress.","authors":"Wenxuan Bai, Tiebin Jiang, Lanlan Tang, Chuhan Shao, Mamingxi Wei, Zisai Wang, Mingyi Zhao","doi":"10.1016/j.exphem.2025.104833","DOIUrl":"https://doi.org/10.1016/j.exphem.2025.104833","url":null,"abstract":"<p><p>Teaser Abstract: Although there has been a large amount of reviews focusing on the relation between gut microbiome and the major complications after allogeneic hematopoietic stem-cell transplantation (allo-HSCT), few review have referred the role of oxidative stress in this process. The manuscript elucidates the mechanism of oxidative stress on allo-HSCT complications, summarize the interaction between GM and oxidative stress in the body, and highlight the role of GM regulation of oxidative stress in allo-HSCT complications. We hope to offer ideas to clinicians formulating new prophylaxis and treatment strategies of allo-HSCT complications. Finally, we would like to make the following declarations: The work described has not been submitted elsewhere for publication, in whole or in part, and all the authors listed have approved the manuscript that is enclosed. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a cure for many malignant hematologic and metabolic diseases, whose complications are an unignorable cause of long-term prognosis. Pre-treatment chemoradiotherapy administered before and after transplantation alters the state of the bone marrow hematopoietic microenvironment. Under the stress of hematopoietic injury, a large number of hematopoietic stem cells (HSC) proliferate and differentiate, that produce large amounts of reactive oxygen species (ROS).And the chemotherapeutic pre-treatment drugs themselves also cause oxidative stress(OS),which can indirectly exacerbated OS of the bone marrow microenvironment. The bone marrow hematopoietic microenvironment and local oxidative stress affects the development of infections, relapse, graft-versus-host disease (GVHD), poor graft function (PGF), persistent thrombocytopenia (PT), chronic fatigue syndrome (CFS), bronchiolitis obliterans (BOS), transplant-associated thrombotic microangiopathy (TA-TMA), etc. Recent studies have demonstrated that the gut microbiome (GM) and its metabolites such as short chain fatty acids (SCFAs), secondary bile acids (SBAs), trimethylamine (TMA) and signaling molecules such as H2S and NO can enter the bloodstream through the intestinal epithelium and reach all parts of the body. This review describes the impact of oxidative stress on the development of allo-HSCT complications. In this paper, we will elucidate the mechanism of oxidative stress on allo-HSCT complications, summarize the interaction between GM and oxidative stress in the body, and highlight the role of GM regulation of oxidative stress in allo-HSCT complications, so as to offer new strategies for the prevention and treatment of allo-HSCT complications.</p>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":" ","pages":"104833"},"PeriodicalIF":2.5,"publicationDate":"2025-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144309736","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}

{"title":"Mer receptor expression promotes multiple myeloma disease development via a cell-extrinsic mechanism.","authors":"Justine R Clark, Vasilios Panagopoulos, Jacqueline E Noll, Krzysztof M Mrozik, Alanah L Bradey, Peter I Croucher, Andrew C W Zannettino, Kate Vandyke, Duncan R Hewett","doi":"10.1016/j.exphem.2025.104842","DOIUrl":"https://doi.org/10.1016/j.exphem.2025.104842","url":null,"abstract":"<p><p>Multiple myeloma (MM) is an incurable haematological malignancy characterised by the uncontrolled proliferation of bone marrow resident plasma cells (PCs). Two members of the TAM (TYRO3, AXL and MER) receptor family have previously been implicated in distinct aspects of neoplastic PC biology. AXL expression in MM PCs has been associated with induction of a dormant, non-cycling state within the bone marrow, whereas expression of MER has been implicated in PC proliferation and survival. Here, generation of single TAM receptor expressing 5TGM1 murine MM cell lines enabled the individual functional assessment of the effects of Axl and Mer receptor expression on MM development. Axl expression did not affect proliferation, cell cycling, or stromal cell induced dormancy in vitro. Development of 5TGM1 tumours in C57BL/KaLwRij mice was also unaltered by Axl expression. By contrast, Mer expression conferred an increase in cell proliferation to 5TGM1 cells in vitro, and increased 5TGM1 tumour burden in C57BL/KaLwRij mice. The pro-tumourigenic properties of Mer were only observed following intravenous cell delivery into mice with an intact adaptive immune system. Thus, Axl is neither necessary nor sufficient for induction of MM cancer cell dormancy, whereas Mer remains a promising target for therapeutic intervention in MM patients. Teaser abstract: Multiple myeloma (MM) is an incurable haematological malignancy of plasma cells (PCs). Two members of the TAM (TYRO3, AXL and MER) receptor family have previously been implicated in distinct aspects of MM PC biology. AXL expression in MM PCs has been associated with induction of dormancy, whereas expression of MER has been implicated in PC proliferation and survival. Using mouse myeloma cell lines expressing single TAM receptors, we demonstrate that Axl is neither necessary nor sufficient for induction of MM cancer cell dormancy, whereas Mer promotes tumour development and remains a promising therapeutic target in MM patients.</p>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":" ","pages":"104842"},"PeriodicalIF":2.5,"publicationDate":"2025-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144309787","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}

{"title":"Gene Regulatory Complexes: their role and regulation across normal and malignant haematopoiesis.","authors":"Gina Sangha, Brian Jp Huntly","doi":"10.1016/j.exphem.2025.104821","DOIUrl":"https://doi.org/10.1016/j.exphem.2025.104821","url":null,"abstract":"<p><p>Transcription is regulated in a multitude of ways to ensure lineage- and context-specific gene expression in a co-ordinated fashion. Haematopoiesis is an exemplar process for studying the mechanisms of tightly regulated activation and repression of gene expression programmes by transcription and gene regulatory complexes. These complexes act by post-translational modification of histones and non-histone proteins, epigenetic modifications of DNA, ATP-dependent chromatin remodelling, scaffolding and recruitment of combinatorial protein complexes and alteration of three-dimensional genome conformation to bring about lineage-specific gene expression. This review focusses on the function of these gene regulatory complexes in haematopoiesis and how they are hijacked in Acute Myeloid Leukaemia, highlighting therapeutic progress and opportunities.</p>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":" ","pages":"104821"},"PeriodicalIF":2.5,"publicationDate":"2025-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144309786","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}

{"title":"Advances of RARα fusion genes in acute promyelocytic leukemia.","authors":"Ao Zhang, Shaowei Qiu","doi":"10.1016/j.exphem.2025.104822","DOIUrl":"https://doi.org/10.1016/j.exphem.2025.104822","url":null,"abstract":"<p><p>Retinoic acid receptorα (RARα) is a ligand-dependent transcription factor that dimerizes with retinoid X receptor α (RXRα) to activate target gene promoters, playing a critical role in normal hematopoiesis and granulocyte differentiation. The translocation of chromosomes 15 and 17 generates the PML-RARA fusion gene, the master driver of acute promyelocytic leukemia (APL). The PML-RARα oncoprotein exerts two major effects: transcriptional repression and disruption of PML function. The introduction of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) has significantly improved the complete remission rate in APL, making it a highly treatable disease. However, resistance to ATRA/ATO and the emergence of variant fusion genes remain significant challenges to improving APL prognosis. This review provides an overview of the physiological role of retinoid nuclear receptor signaling in hematopoiesis, the pathological mechanisms of PML-RARα in APL, the pharmacological effects of ATRA/ATO, and the variant translocations identified in APL. We aim to provide innovative research perspectives and insights that may be applicable to other hematopoietic malignancies.</p>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":" ","pages":"104822"},"PeriodicalIF":2.5,"publicationDate":"2025-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144257689","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}

{"title":"Ex vivo modelling reveals low levels of CKS1 inhibition boost haematopoiesis via AKT/Foxo1 signalling","authors":"Juliana Fabiani Miranda ,&nbsp;Adam Rogerson ,&nbsp;Megan Guthrie ,&nbsp;Kimrun Kaur ,&nbsp;Emma Apperley ,&nbsp;Mary Catherine Dunne ,&nbsp;Navin Shridokar ,&nbsp;Anjum Khan ,&nbsp;William Grey","doi":"10.1016/j.exphem.2025.104768","DOIUrl":"10.1016/j.exphem.2025.104768","url":null,"abstract":"<div><div>Hematopoietic stem cells (HSCs) are rare cells residing at the top of the haematopoietic hierarchy capable of reconstituting all blood cell populations through their ability of self-renewal and differentiation. Their ability to maintain haematopoiesis can be majorly depleted by chemotherapeutic agents, leading to a long-term bone marrow injury. However, pre-clinical studies have focused on the acute effects of chemotherapy, leaving the lasting impact on healthy cells poorly understood. To study this, we combined rapid <em>ex vivo</em> models to study the long-term/late-stage effects of a cyclin-dependent kinase subunit 1 (CKS1) inhibitor. Inhibition of CKS1 has been shown to protect healthy HSCs from chemotherapy during acute myeloid leukaemia, and here we show a dose-dependent role of long-term CKS1 inhibition on haematopoiesis, either boosting B lymphopoiesis or ablating HSC proliferation capacity, dependent on the context. Mechanistically, low doses of the CKS1 inhibitor (CKS1i) affects AKT-Foxo1 signalling potentiating B-cell differentiation, but impairing HSC proliferation. These results reveal a novel role for CKS1 in boosting B lymphopoiesis and propose the use of rapid <em>ex vivo</em> models to investigate the long-term effects of chemotherapeutic treatments targeting HSCs with the potential of reducing late adverse effects.</div></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"146 ","pages":"Article 104768"},"PeriodicalIF":2.5,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751821","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}

{"title":"IFC Editorial Board","authors":"","doi":"10.1016/S0301-472X(25)00094-3","DOIUrl":"10.1016/S0301-472X(25)00094-3","url":null,"abstract":"","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"146 ","pages":"Article 104803"},"PeriodicalIF":2.5,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144255126","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}

{"title":"Balancing Hematopoietic Stem Cell Self-renewal and Differentiation Activities Throughout Ontogeny and Aging.","authors":"Masayuki Yamashita, Jingjing Li, Vu L Tran, Myriam L R Haltalli, Shannon McKinney-Freeman, Toshio Suda","doi":"10.1016/j.exphem.2025.104820","DOIUrl":"https://doi.org/10.1016/j.exphem.2025.104820","url":null,"abstract":"<p><p>During fetal development, lifelong hematopoietic stem cells (HSCs) emerge from hemogenic endothelium as a part of the intra-arterial hematopoietic clusters. These definitive HSCs are deemed to colonize and expand in the fetal liver, migrate to the bone marrow, and produce mature blood cells throughout life. However, emerging lines of evidence have challenged this paradigm, and alternative models have been proposed. Moreover, recent studies have revealed expansion of HSCs during aging, which seems counterintuitive to their age-dependent reduction in regenerative capacity. Here, we summarize emerging views on hematopoietic ontogeny and aging, which was the focus of the Summer 2024 International Society for Experimental Hematology (ISEH) webinar. Teaser Abstract: During fetal development, lifelong hematopoietic stem cells (HSCs) emerge from hemogenic endothelium as a part of the intra-arterial hematopoietic clusters. These definitive HSCs are deemed to colonize and expand in the fetal liver, migrate to the bone marrow, and produce mature blood cells throughout life. However, emerging lines of evidence have challenged this paradigm, and alternative models have been proposed. Moreover, recent studies have revealed expansion of HSCs during aging, which seems counterintuitive to their age-dependent reduction in regenerative capacity. Here, we summarize emerging views on hematopoietic ontogeny and aging.</p>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":" ","pages":"104820"},"PeriodicalIF":2.5,"publicationDate":"2025-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144208072","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}

{"title":"Peposertib suppresses generation of FLT3-internal tandem duplication formed by contralateral double nicks.","authors":"Shota Yoshida, Masahiro Onozawa, Shota Yokoyama, Toshihiro Matsukawa, Hideki Goto, Shinsuke Hirabayashi, Takeshi Kondo, Daigo Hashimoto, Yasuhito Onodera, Takanori Teshima","doi":"10.1016/j.exphem.2025.104819","DOIUrl":"https://doi.org/10.1016/j.exphem.2025.104819","url":null,"abstract":"<p><p>FLT3-internal tandem duplication (ITD) is the most frequent gene mutation in acute myeloid leukemia. The consequences of FLT3-ITD have been analyzed in detail; however, the molecular mechanisms underlying FLT3-ITD generation have remained to be elucidated. We analyzed FLT3-ITDs in clinical samples using deep sequencing and identified not only oligoclonal ITDs but also rare deletion clones clustered at the palindrome-like sequence at FLT3 exon 14. We hypothesized that FLT3 exon 14 is genetically unstable due to the palindrome-like sequence at the region and that genomic damage at the site initiates FLT3-ITD formation. We used CRISPR/Cas9 to induce DNA damage for creating artificial FLT3-ITDs in human and mouse cell lines. We found that double nicks on the adjacent contralateral strand most efficiently generate ITDs. The artificial ITDs resembled clinical ITDs in the length distribution and characteristics at the joint. We further compared the inhibitory effects of olaparib and peposertib, specific inhibitors of single-strand break (SSB) and DSB repair, respectively. Peposertib remarkably reduced ITD formation, but olaparib did not affect the mutation pattern. The findings indicated that non-homologous end joining has a crucial role in the generation of ITDs. Our data shed light to the new role of peposertib, which potentially suppress generation of de-novo FLT3-ITDs caused by mis-repair event of the DNA damages in clinical course. Teaser Abstract: FLT3-ITD is the most common mutation in AML, yet its origins remain unclear. Using deep sequencing, we identified rare deletion clones clustering at a palindrome-like sequence in FLT3 exon 14, suggesting genetic instability. CRISPR/Cas9-induced DNA damage revealed that double nicks efficiently generate ITDs, resembling clinical cases. Peposertib, a DNA-PKcs inhibitor, significantly reduced ITD formation, highlighting the role of non-homologous end joining. Our findings suggest a potential therapeutic approach to prevent de novo FLT3-ITDs in AML.</p>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":" ","pages":"104819"},"PeriodicalIF":2.5,"publicationDate":"2025-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144208073","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}

{"title":"FOXP1 contributes to murine hematopoietic stem cell functionality.","authors":"Françoise Levavasseur, Samia Oussous, Alessandro Framarini, Ismael Boussaid, Panhong Gou, Zubaidan Tuerdi, Iman Litchy Boueya, Helyette Hoffner, Marta De Almeida, Morgane Le Gall, Haley Tucker, Stéphane Giraudier, Didier Bouscary, Michaela Fontenay, Diana Passaro, Isabelle Dusanter-Fourt, Evelyne Lauret","doi":"10.1016/j.exphem.2025.104815","DOIUrl":"https://doi.org/10.1016/j.exphem.2025.104815","url":null,"abstract":"<p><p>Transcription factor forkhead box P1 (FOXP1) is a key regulator of immune cell functions. We have shown that FOXP1 contributes to the expansion of human hematopoietic stem/progenitor (HSPC) and acute myeloid leukaemia cells. Here, we investigated the role of FOXP1 in early adult mouse hematopoiesis in vivo. We showed that loss of hematopoietic-specific FOXP1 expression leads to attrition of the HSC and multipotent progenitor (MPP)-1 compartment in parallel with enhancement of myeloid-biased MPP3 in adult bone marrow and fetal liver. Transplantation experiments confirmed that FOXP1-deficient bone marrow had an intrinsic reduced HSC compartment. FOXP1-deficient MPP compartments also showed enhanced proliferation with G0 phase reduction. Transcriptome analyses revealed that FOXP1-deficient HSC exhibited reduced stemness and enhanced expression of cell proliferation pathways. Thus, our current results reveal the important contribution of FOXP1 in early murine hematopoiesis through HSC maintenance, limited expansion of all MPP compartments and restriction of early myeloid commitment in vivo.</p>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":" ","pages":"104815"},"PeriodicalIF":2.5,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144191700","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}

{"title":"Intrabone marrow diversity of endothelial cells and its impact on hematopoietic stem cell development and maintenance.","authors":"Shota Shimizu, Yoshiaki Kubota","doi":"10.1016/j.exphem.2025.104817","DOIUrl":"10.1016/j.exphem.2025.104817","url":null,"abstract":"<p><p>In addition to supplying oxygen and nutrients, blood vessels secrete paracrine molecules known as angiocrine factors to promote tissue homeostasis and repair. The bone marrow (BM) vasculature in long bones has differing properties between the diaphysis, metaphysis, and epiphysis in terms of its morphology, plasticity, perivascular cellular components, and angiocrine profiles. Blood vessel formation is linked with bone formation through paracrine interactions between endothelial cells (ECs) and osteolineage cells, so-called angiogenic-osteogenic coupling. ECs also play essential roles in the maintenance of hematopoietic stem cells (HSCs) by forming vascular niches together with perivascular stromal cells. Recent studies highlighted the heterogeneity of vascular niches at different bone regions, suggesting that HSCs are regulated by locally distinct mechanisms. Here, we provided an overview of the BM vasculature and discussed how the heterogeneous vasculature contributes to bone formation and HSC maintenance.</p>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":" ","pages":"104817"},"PeriodicalIF":2.5,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144173229","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}