Experimental hematology最新文献

{"title":"Cis- and trans-regulation of Irf8 enhancers during dendritic cell development.","authors":"Akira Nishiyama, Tomohiko Tamura","doi":"10.1016/j.exphem.2025.104858","DOIUrl":"10.1016/j.exphem.2025.104858","url":null,"abstract":"<p><p>Dendritic cells (DCs) are mononuclear phagocytes that play a crucial role in the immune system by mediating innate and adaptive immunity. DC differentiation requires the establishment of DC-specific gene expression regulated by lineage-specific transcription factors. Recent studies have reported a series of transcription factors essential for DC differentiation, as well as the regulatory circuit composed of these transcription factors. Among these transcription factors, interferon regulatory factor 8 (IRF8) is pivotal for the differentiation of type 1 classical DCs (cDC1s). IRF8 establishes the enhancer landscape at the progenitor stage and also regulates the higher-order chromatin structure of cDC1-specific genes. Furthermore, the cell fate within the myeloid lineages is determined in an IRF8 dose-dependent manner. The enhancers that govern Irf8 expression have been identified and extensively studied. Notably, Irf8 expression is regulated by a complex interplay among 3' enhancers, each of which has a differentiation stage-specific effect. In this review, we discuss recent advances in our understanding of the regulatory mechanisms of IRF8 expression underlying cDC1 development.</p>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":" ","pages":"104858"},"PeriodicalIF":2.1,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144667457","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":"Upfront Menin-inhibitor resistance in multiply pretreated leukemias.","authors":"Leila Mahdavi, Fatemeh Alikarami, Haley Goodrow, Alexandra Lenard, Simone S Riedel, Clara Libbrecht, Isabel Bowser, Sarah K Tasian, Catherine D Falkenstein, Bryan Manning, Sarah Skuli, Martin P Carroll, Gerald Wertheim, Sheng F Cai, Gerard McGeehan, Sixiang Yu, Junwei Shi, Hongbo M Xie, Kathrin M Bernt","doi":"10.1016/j.exphem.2025.105268","DOIUrl":"https://doi.org/10.1016/j.exphem.2025.105268","url":null,"abstract":"<p><p>Inhibitors of the Menin-KMT2A interaction are promising agents for the treatment of KMT2A-rearranged (KMT2A-r) leukemias. We evaluated Menin inhibition in patient derived xenografts of KMT2A-r leukemias with high-risk features. Three AMLs with high-risk fusion partners (MLLT10, MLLT4) and two infant ALL samples were sensitive to Menin inhibition. We also evaluated serial samples from two patients with multiply relapsed ALL. We found that highly pretreated KMT2A::AFF1 ALL samples were much less sensitive compared to cells obtained earlier in the same patients' disease course. Since none of the patients had been treated with a Menin inhibitor, resistance in these highly pretreated samples was acquired in the absence to Menin inhibitor exposure. Transcriptomic analysis documented sustained on-target efficacy towards the canonical targets in the Menin-inhibitor in resistant cells. Targeted genomic analysis documented the emergence of multiple co-mutations, including RAS pathway and TP53 mutations, although neither was sufficient to induce Menin-inhibitor resistance in vitro. Downregulation of KMT3D may account for resistance in one patients; inactivation of KMT2C/D has been reported to result in Menin inhibitor resistance, and KMT2C-edited cells from this patient were selected for in VTP containing growth conditions. Future studies will need to clarify more broadly which genomic/epigenomic alterations drive upfront resistance. Regardless of mechanism, our data supports using Menin-inhibitors upfront or in early lines of therapy before substantial genomic or epigenomic evolution has occurred.</p>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":" ","pages":"105268"},"PeriodicalIF":2.1,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145198910","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":"Building a transparent and functional laboratory culture: guidelines for creating a Laboratory Handbook for principal investigators.","authors":"Charles E de Bock, Katherine S Bridge, Nick van Gastel, Hélène F E Gleitz, Lev Kats, Katherine Y King, Kellie R Machlus, Bethan Psaila, Vanessa Scanlon, George P Souroullas, Konstantinos D Kokkaliaris","doi":"10.1016/j.exphem.2025.105265","DOIUrl":"10.1016/j.exphem.2025.105265","url":null,"abstract":"","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":" ","pages":"105265"},"PeriodicalIF":2.1,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145112350","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":"Three-dimensional genome reorganization in hematopoietic stem cells.","authors":"Akihiro Nakajima, Keisuke Kirito, Mio Nakanishi, Naoya Takayama","doi":"10.1016/j.exphem.2025.105249","DOIUrl":"10.1016/j.exphem.2025.105249","url":null,"abstract":"<p><p>Hematopoietic stem cells (HSCs) possess unique characteristics that distinguish them from other hematopoietic progenitor cells, including self-renewal capacity, multipotency, stress response, metabolism, and deep quiescence. Recent advances have significantly enhanced our understanding of the epigenomic states that define these properties. HSCs undergo profound changes in their three-dimensional (3D) genome reorganization throughout development, differentiation, and responses to stimuli. Recent advancements in chromatin conformation capture techniques that require only a small number of cells have provided detailed insights into these dynamic processes. This review explored the latest discoveries in the 3D genome reorganization in HSCs, with a focus on chromatin remodeling during key transitions, including fetal-to-adult development, quiescence-to-activation, differentiation, and aging. We discussed the roles of key transcription factors, epigenetic modifiers, and structural proteins in shaping the 3D genome landscape. Additionally, we examined how alterations in the 3D genome organization impact HSC function and dysfunction in hematologic disorders. Finally, we highlighted future directions in this rapidly evolving field, emphasizing the potential implications of 3D genome research for targeted therapies in hematology.</p>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":" ","pages":"105249"},"PeriodicalIF":2.1,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145102873","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":"A 30-gene classifier distinguishes low-risk MDS HSPCs from healthy HSPCs.","authors":"Pawan Bhat, Joseph C Van Amburg, Chad R Potts, Thomas J Gracie, Justin A Cartailler, Alyssa C Parker, Michael R Savona, Rui Lu, Stanley C Lee, Robert S Welner, Alexander G Bick, P Brent Ferrell","doi":"10.1016/j.exphem.2025.105252","DOIUrl":"10.1016/j.exphem.2025.105252","url":null,"abstract":"","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":" ","pages":"105252"},"PeriodicalIF":2.1,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145091321","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":"An engineered IgM antibody targeting CD20 has enhanced complement-dependent cytotoxicity compared with an IgG.","authors":"Kevin C Hart, Paul R Hinton, Marigold Manlusoc, Kevin B Carlin, Samuel Schneider, Maya F Kotturi, Ramesh Baliga, Bruce A Keyt","doi":"10.1016/j.exphem.2025.105250","DOIUrl":"10.1016/j.exphem.2025.105250","url":null,"abstract":"<p><p>Complement-dependent cytotoxicity (CDC) is one of the main mechanisms of action for approved therapeutic anti-CD20 immunoglobulin (Ig) G antibodies, including rituximab, ofatumumab, and ocrelizumab, in the treatment of B-cell lymphoma patients. However, resistance to these therapies inevitably develops in patients, and thus novel antibody approaches are needed. Here, we described the CDC activity of an anti-CD20 IgM in comparison to an anti-CD20 IgG. We applied live-cell imaging and kinetic analysis to measure CDC activity in real time. Through this imaging platform, we demonstrated that an IgM antibody exhibited more potent and faster target cell killing through CDC compared with an IgG antibody. Additionally, an IgM antibody was more effective at killing target cells with low antigen density, in low levels of complement, and in the presence of high complement inhibitor expression. An anti-CD20 IgM also showed superior CDC against ex vivo tumor samples from a patient with B-cell lymphoma. These preclinical studies demonstrated the potential of an anti-CD20 IgM-based therapeutic antibody having superior CDC in B-cell lymphoma compared with a traditional IgG antibody.</p>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":" ","pages":"105250"},"PeriodicalIF":2.1,"publicationDate":"2025-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145074831","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":"A xeno-free red blood cell differentiation formula models sickle cell disease from somatically sourced patient iPSCs.","authors":"Ashlee J Conway, Tolulope O Rosanwo, Thomas E Williamson, Samuel Landry, Melissa A Kinney, Martha A Clark, Linda T Vo, R Grant Rowe, William Marion, Yosra Zhang, Nathaniel K Mullin, Michael Shi, Natasha M Archer, Matthew M Heeney, Thorsten M Schlaeger, Daniel E Bauer, Manoj T Duraisingh, Carlo Brugnara, Trista E North, George Q Daley","doi":"10.1016/j.exphem.2025.105264","DOIUrl":"10.1016/j.exphem.2025.105264","url":null,"abstract":"<p><p>Human-derived induced pluripotent stem cells (iPSCs) are an invaluable resource in both two-dimensional (2D) and three-dimensional (3D) tissue engineering due to their multilineage potential in culture systems. To date, modeling red blood cell (RBC) disorders such as sickle cell disease (SCD) from iPSCs has been challenging due to the tendency for differentiation protocols to produce immature erythrocytes that lack robust β-globin expression and enucleate poorly. Here, we demonstrated an optimized three-stage erythroid differentiation protocol that generates enucleated, β-globin-expressing RBCs from somatically sourced iPSCs, derived from both healthy donors and patients with homozygous SCD. Induced RBCs (iRBCs) present phenotypically as GlyA⁺Band3⁺CD71^lo and express adult hemoglobin tetramers. SCD iRBCs displayed sickling phenotypes in vitro when exposed to hypoxia. RNA-sequencing analysis of iPSC-derived SCD reticulocytes revealed dysregulated disease-relevant molecular pathways, suggesting future therapeutic avenues of investigation can be identified in this model. We further refined the protocol into a xeno-free formulation by replacing albumin sources with polyvinyl alcohol (PVA), significantly enhancing iRBC production without loss of terminal maturation. The ability to generate patient-specific iRBCs from somatic cell sources provides a valuable in vitro tool for the study of SCD and the development of novel treatments.</p>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":" ","pages":"105264"},"PeriodicalIF":2.1,"publicationDate":"2025-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145074842","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":"Optimal ex vivo production of functional neutrophils is dependent on the source of CD34+ human hematopoietic progenitors.","authors":"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, Vince Ho, David B Sykes, Michael K Mansour","doi":"10.1016/j.exphem.2025.105251","DOIUrl":"10.1016/j.exphem.2025.105251","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":" ","pages":"105251"},"PeriodicalIF":2.1,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145063867","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":"Platelets loaded with alteplase exert fibrinolytic activity in human whole blood and plasma","authors":"Masataka Inoue ,&nbsp;Masahiro Ohwada ,&nbsp;Teruhiko Negishi ,&nbsp;Nobuo Watanabe","doi":"10.1016/j.exphem.2025.105248","DOIUrl":"10.1016/j.exphem.2025.105248","url":null,"abstract":"<div><div>The utilization of alteplase for the management of intracerebral thromboembolism is associated with an elevated risk of intracerebral hemorrhage. To mitigate this risk, we investigated the fibrinolytic effect of alteplase-loaded platelets as a preliminary step in the development of a biocompatible drug delivery system (DDS). In this context, we demonstrated that platelet loaded with alteplase exhibited thrombolytic efficacy. Therefore, a drug DDS that employs alteplase-loaded platelets may offer a promising avenue for the development of a more biocompatible and less invasive thrombolytic therapy.</div></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"151 ","pages":"Article 105248"},"PeriodicalIF":2.1,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058484","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":"KMT2A-rearranged leukemia: from mechanism to drug development","authors":"Patricia Ernst ,&nbsp;Perpetual S.Kyei ,&nbsp;Akihiko Yokoyama","doi":"10.1016/j.exphem.2025.105247","DOIUrl":"10.1016/j.exphem.2025.105247","url":null,"abstract":"<div><div>Gene rearrangements of the human mixed lineage leukemia (<em>MLL)</em> gene (also known as <em>KMT2A</em>) generate multiple fusion oncoproteins, which cause leukemia with poor prognosis. MLL is an epigenetic regulator that reads and writes epigenetic information and has an evolutionarily conserved role in maintaining expression of <em>Homeotic</em> (<em>HOX</em>) genes during embryonic development. Most <em>MLL</em> gene rearrangements found in leukemia generate a constitutively active version of the wild-type protein, which causes overexpression of <em>HOX</em> and other genes and leukemic transformation of normal hematopoietic progenitors. Elucidating the molecular mechanisms underlying how MLL activates gene expression and how gene rearrangements affect this gene-regulating activity provided therapeutic opportunities to block fusion oncoprotein-specific activities. One uniform molecular dependency of MLL fusion oncoproteins is its interaction with the chromatin-binding partner MENIN that is essential to maintain leukemic transformation. MENIN inhibitors that interfere with the MLL–MENIN interaction have been developed and are now entering clinical practice. Also, the MLL complex physically interacts with several histone acetyl transferases (HATs), including MOZ/MORF, HBO1, and EP300/CREBBP to effect MLL–MENIN-dependent gene activation. Aberrant recruitment of these HATs and other transcriptional effector complexes are key differences between MLL and MLL fusion oncoproteins. In this review, we first summarized our current understanding of wild-type MLL function and the aberrant function of its oncogenic variants. We then discussed in detail how chromosomal translocations generate constitutive-active forms of MLL and categorize them into five major classes. We touched on the collaborative gene activation by MLL and specific interacting HATs. Lastly, we discussed how these mechanistic insights have led to the development of the first-in-class MENIN inhibitors and discussed efforts to anticipate and treat both genetic and nongenetic mechanisms of resistance.</div></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"151 ","pages":"Article 105247"},"PeriodicalIF":2.1,"publicationDate":"2025-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145023170","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}