Experimental hematology最新文献

{"title":"2020 – A CONSERVED TRANSCRIPTIONAL PROGRAM DICTATES THE ENGRAFTMENT OF EX VIVO EXPANDED HSCS","authors":"Ali Motazedian, Phillip Nguyen, Elanor Wainwright, Enid Lam, Mark Dawson","doi":"10.1016/j.exphem.2026.105548","DOIUrl":"10.1016/j.exphem.2026.105548","url":null,"abstract":"<div><div>Bone marrow transplantation (BMT) is a cornerstone of hematologic cancer therapy, yet engraftment failure and clonal hematopoiesis (CH) remain significant challenges. Although ex vivo expansion of hematopoietic stem cells (HSCs) offers a potential solution, the underlying clonal dynamics remain poorly understood. To investigate the clonal dynamics of ex vivo expanded HSCs, we tracked barcoded HSCs across evolutionarily diverse mouse strains, transplanting identical set of barcoded sister cells into distinct host environments. We found that long-term chimerism depended on both cell dose and intrinsic clonal fitness. Although higher irradiation increased total chimerism without altering the number of engrafting clones, reducing donor cell dose decreased multilineage clones and skewed clonal output toward the B-cell lineage. scRNA-seq revealed that high-output multilineage clones maintain a core stem transcriptomic program (Engraftment Score) conserved across strains. Our data suggest that successful engraftment is restricted to a specific subpopulation within each clone. Clones prone to in vitro differentiation require higher doses to ensure the transfer of competent HSCs, whereas “fit” clones that resist in vitro differentiation repopulate robustly at lower doses. Importantly, pooling independently expanded clones improved chimerism and lineage balance, mitigating CH risk. Although aged HSCs showed diminished fitness and myeloid biased output, engrafted clones had high engraftment score before BMT and utilized the same conserved engraftment program as young cells. Conversely, aged DNMT3A-mutant HSPCs resisted functional decline and exhibited enhanced engraftment. These findings highlight the interplay between intrinsic donor capacity and the host microenvironment and identify a conserved engraftment program as a potential therapeutic target to maximize clonal engraftment.</div></div><div>Bone marrow transplantation (BMT) is a cornerstone of hematologic cancer therapy, yet engraftment failure and clonal hematopoiesis (CH) remain significant challenges. Although ex vivo expansion of hematopoietic stem cells (HSCs) offers a potential solution, the underlying clonal dynamics remain poorly understood. To investigate the clonal dynamics of ex vivo expanded HSCs, we tracked barcoded HSCs across evolutionarily diverse mouse strains, transplanting identical set of barcoded sister cells into distinct host environments. We found that long-term chimerism depended on both cell dose and intrinsic clonal fitness. Although higher irradiation increased total chimerism without altering the number of engrafting clones, reducing donor cell dose decreased multilineage clones and skewed clonal output toward the B-cell lineage. scRNA-seq revealed that high-output multilineage clones maintain a core stem transcriptomic program (Engraftment Score) conserved across strains. Our data suggest that successful engraftment is restricted to a specific subpopulation wit","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"162 ","pages":"Article 105548"},"PeriodicalIF":2.7,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149233963","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":"1025 – EXPLORING THE MEGAVERSE—MEGAKARYOCYTES, PLATELETS AND MYELOPROLIFERATIVE NEOPLASMS","authors":"Beth Psaila","doi":"10.1016/j.exphem.2026.105520","DOIUrl":"10.1016/j.exphem.2026.105520","url":null,"abstract":"<div><div>Megakaryocytes are one of the largest and rarest cells in the human body—with a giant cell size and massive, polyploid nucleus. This confers a tremendous synthetic capacity—and a handful of megakaryocytes are able to release billions of tiny platelets into our bloodstream every day. Platelets, in contrast to their parent megakaryocytes, have no nucleus at all. Despite their lack of a nucleus, we recently discovered that platelets contain a repertoire of DNA fragments acquired during circulation by “hoovering up” cell-free DNA shed by nucleated cells—including cancer cell-derived and free fetal DNA. In our ongoing work, we are exploring how megakaryocytes tolerate the successive rounds of whole genome duplication and the implications of this for their genome stability.</div><div>Megakaryocytes, along with related cells, are major contributors to the disease features and progression of myeloproliferative neoplasms (MPNs)—chronic blood cancers occurring in around 4,000 people in the UK each year. We are interested in how megakaryocytes, MPN stem cells, and the bone marrow stroma interact to drive progression to advanced-stage MPN, in particular myelofibrosis, with an overarching goal of developing more disease-modifying treatments that improve outcomes for patients. To explore this, we have implemented novel experimental platforms, including human organoids. We are currently also using these to unpick the mechanisms that fuel progression and to develop ex vivo systems that evaluate emerging cancer cell-targeting therapies in more relevant human tumor microenvironments.</div></div><div>Megakaryocytes are one of the largest and rarest cells in the human body—with a giant cell size and massive, polyploid nucleus. This confers a tremendous synthetic capacity—and a handful of megakaryocytes are able to release billions of tiny platelets into our bloodstream every day. Platelets, in contrast to their parent megakaryocytes, have no nucleus at all. Despite their lack of a nucleus, we recently discovered that platelets contain a repertoire of DNA fragments acquired during circulation by “hoovering up” cell-free DNA shed by nucleated cells—including cancer cell-derived and free fetal DNA. In our ongoing work, we are exploring how megakaryocytes tolerate the successive rounds of whole genome duplication and the implications of this for their genome stability.</div><div>Megakaryocytes, along with related cells, are major contributors to the disease features and progression of myeloproliferative neoplasms (MPNs)—chronic blood cancers occurring in around 4,000 people in the UK each year. We are interested in how megakaryocytes, MPN stem cells, and the bone marrow stroma interact to drive progression to advanced-stage MPN, in particular myelofibrosis, with an overarching goal of developing more disease-modifying treatments that improve outcomes for patients. To explore this, we have implemented novel experimental platforms, including human organoids. We ","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"162 ","pages":"Article 105520"},"PeriodicalIF":2.7,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149234067","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":"1027 – TARGETING PROTEIN TRANSLATION TO PREEMPT ADAPTATION OF LEUKEMIA CELLS UNDERGOING THERAPY","authors":"Peter van Galen, Yoke Seng Lee, Jingting Lin, Jonathan Good, Mark Wunderlich, Carmen Da Silva, Jenna Thibodeau, Holly Edwards, Prafulla Gokhale, Yubin Ge, Fadi Najm, Peter Miller, Andrew Lane, Courtney Jones","doi":"10.1016/j.exphem.2026.105522","DOIUrl":"10.1016/j.exphem.2026.105522","url":null,"abstract":"<div><div>Recent advances have expanded the arsenal of available treatments for acute myeloid leukemia (AML). However, complete eradication of leukemia cells remains challenging, and resistant subpopulations of cells often persist to drive relapse. The adaptive mechanisms that persister cells use to survive therapy-induced stress remain incompletely understood. Cellular stress induces translation of proteins that promote survival, suggesting that blocking adaptive translation could limit AML cell survival. Here, we presented evidence that inhibition of protein translation can enhance the efficacy of targeted therapies. The translation initiation factor eukaryotic translation initiation factor 4A (eIF4A) promotes translation of transcripts with complex 5` untranslated region (UTR) structures; the inhibitor zotatifin clamps eIF4A onto these 5` UTRs, abrogating their translation. Using ribosome profiling and gene set enrichment analysis, we found that zotatifin reduces translation efficiency of pathways related to oncogenic signaling and the cell cycle. Western blot analysis corroborated these findings and demonstrated the downregulation of factors implicated in resistance to venetoclax-based regimens, including AK strain transforming (AKT), signal transducer and activator of transcription 5 (STAT-5), myeloid cell leukemia 1 (MCL-1), and MYC proto-oncogene, BHLH transcription factor (MYC). Indeed, zotatifin synergistically kills AML cells in vitro when combined with venetoclax or venetoclax + azacitidine, inducing apoptosis across AML genotypes with selectivity toward progenitor-like cells. In three in vivo xenograft models derived from patients with relapsed/refractory AML, including a venetoclax-resistant model, zotatifin plus venetoclax significantly suppressed tumor burden and prolonged survival. Ongoing experiments are evaluating the selectivity of zotatifin for AML compared with healthy cells in vivo and dissecting the specific translational basis of synergy between eIF4A inhibition and venetoclax. Overall, these results support that preempting cellular adaptation via rewiring of the translational landscape can enhance the efficacy of targeted therapies and provide a rationale for clinical implementation of combination therapies with targeted translation inhibitors.</div></div><div>Recent advances have expanded the arsenal of available treatments for acute myeloid leukemia (AML). However, complete eradication of leukemia cells remains challenging, and resistant subpopulations of cells often persist to drive relapse. The adaptive mechanisms that persister cells use to survive therapy-induced stress remain incompletely understood. Cellular stress induces translation of proteins that promote survival, suggesting that blocking adaptive translation could limit AML cell survival. Here, we presented evidence that inhibition of protein translation can enhance the efficacy of targeted therapies. The translation initiation factor eukaryotic translation ","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"162 ","pages":"Article 105522"},"PeriodicalIF":2.7,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149234068","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":"1028 – AGING-RELATED SPATIAL REMODELING OF BONE MARROW HEMATOPOIETIC STEM CELL MICROENVIRONMENTS.","authors":"Konstantinos Kokkaliaris","doi":"10.1016/j.exphem.2026.105523","DOIUrl":"10.1016/j.exphem.2026.105523","url":null,"abstract":"<div><div>Aging is associated with functional decline of hematopoietic stem cells (HSCs) and their supportive bone marrow (BM) microenvironment(s). However, the cumulative effect of biological aging on BM tissue organization in situ remains poorly understood. To address this challenge, we systematically quantified multiple BM and hematopoietic populations in adult, middle-aged, and old mice using three-dimensional (3D) tissue-wide imaging cytometry. We identified spatially distinct hematopoietic microenvironments (HeMs) with distinct cellular composition and quantified their topographic remodeling during aging. We reported that HSCs associate with multiple HeMs, but those that contain most of the repopulation activity are localized in perisinusoidal diaphyseal locations enriched in megakaryocytes although being spatially segregated from all other studied BM populations. Interestingly, we demonstrated that exposure to systemic stress induced persistent BM alterations that recapitulated age-associated phenotypes. Our work provided an integrative framework linking spatial tissue organization with HSC behavior across physiological and stress states.</div></div><div>Aging is associated with functional decline of hematopoietic stem cells (HSCs) and their supportive bone marrow (BM) microenvironment(s). However, the cumulative effect of biological aging on BM tissue organization in situ remains poorly understood. To address this challenge, we systematically quantified multiple BM and hematopoietic populations in adult, middle-aged, and old mice using three-dimensional (3D) tissue-wide imaging cytometry. We identified spatially distinct hematopoietic microenvironments (HeMs) with distinct cellular composition and quantified their topographic remodeling during aging. We reported that HSCs associate with multiple HeMs, but those that contain most of the repopulation activity are localized in perisinusoidal diaphyseal locations enriched in megakaryocytes although being spatially segregated from all other studied BM populations. Interestingly, we demonstrated that exposure to systemic stress induced persistent BM alterations that recapitulated age-associated phenotypes. Our work provided an integrative framework linking spatial tissue organization with HSC behavior across physiological and stress states.</div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"162 ","pages":"Article 105523"},"PeriodicalIF":2.7,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149234069","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":"2028 – MOLECULAR REGULATION OF CELL FATE DIVERGENCE IN ASYMMETRIC DIVISION OF HEMATOPOIETIC STEM CELLS","authors":"Anna Konturek-Ciesla,&nbsp;Aurimas Greicius,&nbsp;Lena Blaase,&nbsp;Jiayan Lin,&nbsp;Florin Schneiter,&nbsp;Yang Zhang,&nbsp;Giovanni D’Angelo,&nbsp;Petra Dittrich,&nbsp;Timm Schroeder","doi":"10.1016/j.exphem.2026.105556","DOIUrl":"10.1016/j.exphem.2026.105556","url":null,"abstract":"&lt;div&gt;&lt;div&gt;Distinct molecular programs guide hematopoietic cell fates but are difficult to study due to cellular heterogeneity arising from different clonal origins and molecular composition. Asymmetric cell division (ACD) offers a controlled system, producing genetically identical sister cells with pre-determined divergent fates. Hematopoietic stem cells (HSCs) undergo ACD, where unequal lysosome inheritance predicts differential metabolic activation in daughters. Here, we study whether lipids and ERK signaling drive early fate divergence in HSC ACD.&lt;/div&gt;&lt;div&gt;Lipid composition can influence cell fates in other cell types. We therefore use imaging mass spectrometry-based lipidomics to profile hematopoietic populations across the developmental hierarchy, generating a single-cell lipidomic map of murine hematopoiesis. We further develop lipiTrack, a pipeline for combined single-cell imaging, tracking, and lipidomics. We find that lipid composition is dynamically regulated during HSC division.&lt;/div&gt;&lt;div&gt;Finally, using time lapse imaging and fluorescence biosensors to quantify single-cell dynamics, we show that HSC ACD daughters are enriched for sustained ERK signaling, which correlates with elevated lysosome signal. Most HSC daughter pairs show divergent ERK signaling, with early metabolic activation mainly in unmatched ACD pairs. Ongoing work examines how response patterns of ERK and other signaling pathways relate to lysosomes.&lt;/div&gt;&lt;div&gt;Together, these findings identify lipid heterogeneity and ERK dynamics as a previously unrecognized regulatory layer in cell fate determination and provide new insights into the molecular control of blood cell development.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;Distinct molecular programs guide hematopoietic cell fates but are difficult to study due to cellular heterogeneity arising from different clonal origins and molecular composition. Asymmetric cell division (ACD) offers a controlled system, producing genetically identical sister cells with pre-determined divergent fates. Hematopoietic stem cells (HSCs) undergo ACD, where unequal lysosome inheritance predicts differential metabolic activation in daughters. Here, we study whether lipids and ERK signaling drive early fate divergence in HSC ACD.&lt;/div&gt;&lt;div&gt;Lipid composition can influence cell fates in other cell types. We therefore use imaging mass spectrometry-based lipidomics to profile hematopoietic populations across the developmental hierarchy, generating a single-cell lipidomic map of murine hematopoiesis. We further develop lipiTrack, a pipeline for combined single-cell imaging, tracking, and lipidomics. We find that lipid composition is dynamically regulated during HSC division.&lt;/div&gt;&lt;div&gt;Finally, using time lapse imaging and fluorescence biosensors to quantify single-cell dynamics, we show that HSC ACD daughters are enriched for sustained ERK signaling, which correlates with elevated lysosome signal. Most HSC daughter pairs show divergent ERK signaling, with early metabolic ac","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"162 ","pages":"Article 105556"},"PeriodicalIF":2.7,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149234123","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":"1032 – DECODING THE CLONAL EVOLUTION OF MYELOID MALIGNANCY THROUGH IPSC REPROGRAMMING","authors":"Eirini Papapetrou","doi":"10.1016/j.exphem.2026.105527","DOIUrl":"10.1016/j.exphem.2026.105527","url":null,"abstract":"<div><div>Our laboratory pioneered human induced pluripotent stem cells (iPSCs) as models of myeloid malignancies. By combining patient cell reprogramming with clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-assoiciated protein 9 (Cas9)-mediated precise gene editing, we develop genetic models of myeloid leukemias and preleukemia and exploit the unique capabilities they offer: the ability to perform genotype-to-phenotype studies and to study the oncogenic mechanisms of driver mutations in a faithful cellular and genomic environment; to obtain large numbers of homogeneous cells for multiomics analyses and genetic and small molecule screens; and to validate findings through functional assays in isogenic conditions. With these models, we are uncovering novel disease mechanisms and identifying new therapeutic targets. We are particularly striving to understand the events underlying the progression from premalignant conditions—clonal hematopoiesis and inherited myeloid malignancy predisposition syndromes—to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). This presentation will provide an overview of iPSC models of the clonal evolution of AML and discuss recent findings on the role of RAS pathway mutations in disease progression and therapy resistance in AML, as well as the role of type I interferon signaling in the clonal fitness of <em>TET2</em>-mutated hematopoietic stem and progenitor cells.</div></div><div>Our laboratory pioneered human induced pluripotent stem cells (iPSCs) as models of myeloid malignancies. By combining patient cell reprogramming with clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-assoiciated protein 9 (Cas9)-mediated precise gene editing, we develop genetic models of myeloid leukemias and preleukemia and exploit the unique capabilities they offer: the ability to perform genotype-to-phenotype studies and to study the oncogenic mechanisms of driver mutations in a faithful cellular and genomic environment; to obtain large numbers of homogeneous cells for multiomics analyses and genetic and small molecule screens; and to validate findings through functional assays in isogenic conditions. With these models, we are uncovering novel disease mechanisms and identifying new therapeutic targets. We are particularly striving to understand the events underlying the progression from premalignant conditions—clonal hematopoiesis and inherited myeloid malignancy predisposition syndromes—to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). This presentation will provide an overview of iPSC models of the clonal evolution of AML and discuss recent findings on the role of RAS pathway mutations in disease progression and therapy resistance in AML, as well as the role of type I interferon signaling in the clonal fitness of <em>TET2</em>-mutated hematopoietic stem and progenitor cells.</div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"162 ","pages":"Article 105527"},"PeriodicalIF":2.7,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149234157","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":"2005 – SAMD9 GAIN-OF-FUNCTION DISRUPTS HEMATOPOIESIS AND IS PARTIALLY RESCUED BY SECONDARY LOSS-OF-FUNCTION IN IPSC MODELS","authors":"Joan Pera,&nbsp;Eric Torralba-Sales,&nbsp;Raimon Bundo-Ruiz,&nbsp;Maria Magallon-Mosella,&nbsp;Damia Romero-Moya,&nbsp;Oskar Marin-Bejar,&nbsp;Clara Berenguer-Balaguer,&nbsp;Lorenzo Pasquali,&nbsp;Albert Català,&nbsp;Marcin Wlodarski,&nbsp;Alessandra Giorgetti","doi":"10.1016/j.exphem.2026.105533","DOIUrl":"10.1016/j.exphem.2026.105533","url":null,"abstract":"&lt;div&gt;&lt;div&gt;Germline SAMD9 gain-of-function (GoF) variants cause bone marrow failure and predispose to myelodysplastic neoplasms, yet the mechanisms of hematopoiesis dysfunction remain unclear. We generated an iPSC model carrying a homozygous germline SAMD9 GoF mutation and a secondary loss-of-function (LoF) event mimicking somatic rescue observed in two-thirds of patients, enabling analysis of both sustained SAMD9 hyperactivity and compensatory inactivation.&lt;/div&gt;&lt;div&gt;Upon hematopoietic differentiation, SAMD9 GoF caused accumulation of hematopoietic (HPC, CD34&lt;sup&gt;+&lt;/sup&gt;CD43&lt;sup&gt;+&lt;/sup&gt;) and immature myeloid progenitors (CD33&lt;sup&gt;+&lt;/sup&gt;CD43&lt;sup&gt;+&lt;/sup&gt;), with increased apoptosis and reduced cell cycle activity, suggesting an early progenitor differentiation block. CFU assay confirmed reduced mature colony output. TNF-α further impaired HPC development, suggesting that inflammatory signaling exacerbates defects and may drive long-term HSPC exhaustion.&lt;/div&gt;&lt;div&gt;Transcriptomic analysis showed that SAMD9 GoF upregulated inflammatory genes (CD74, STAT2), TP53 pathway genes (CDKN1A, SESN1), and myeloid progenitor-associated markers (SPINK2, GATA1). Under TNF-α exposure, these changes were reinforced, with increased TNF, CCL2, and TAL1, alongside downregulation of genes involved in cell cycle, DNA repair, and hematopoietic differentiation, supporting a model of impaired quiescence, reduced proliferation, and defective lineage commitment.&lt;/div&gt;&lt;div&gt;In contrast, SAMD9 LoF restored hematopoiesis under steady state conditions, preserving colony-forming capacity, reducing apoptosis, and protecting the hematopoietic compartment under TNF-α exposure. LoF led to an enrichment of myeloid differentiation and HSC maintenance programs, together with reduced apoptosis-related genes compared with GoF cells, suggesting a partial restoration of hematopoietic balance. Altogether, our iPSC-based platform recapitulates key molecular and cellular features of SAMD9-associated MDS.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;Germline SAMD9 gain-of-function (GoF) variants cause bone marrow failure and predispose to myelodysplastic neoplasms, yet the mechanisms of hematopoiesis dysfunction remain unclear. We generated an iPSC model carrying a homozygous germline SAMD9 GoF mutation and a secondary loss-of-function (LoF) event mimicking somatic rescue observed in two-thirds of patients, enabling analysis of both sustained SAMD9 hyperactivity and compensatory inactivation.&lt;/div&gt;&lt;div&gt;Upon hematopoietic differentiation, SAMD9 GoF caused accumulation of hematopoietic (HPC, CD34&lt;sup&gt;+&lt;/sup&gt;CD43&lt;sup&gt;+&lt;/sup&gt;) and immature myeloid progenitors (CD33&lt;sup&gt;+&lt;/sup&gt;CD43&lt;sup&gt;+&lt;/sup&gt;), with increased apoptosis and reduced cell cycle activity, suggesting an early progenitor differentiation block. CFU assay confirmed reduced mature colony output. TNF-α further impaired HPC development, suggesting that inflammatory signaling exacerbates defects and may drive long-term HSPC exhaustion.&lt;/div&gt;&lt;div&gt;Transcriptomic analysis show","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"162 ","pages":"Article 105533"},"PeriodicalIF":2.7,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149233825","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":"1026 – FROM STEM CELL STATES TO STEM CELL FLUX","authors":"Berthold Gottgens","doi":"10.1016/j.exphem.2026.105521","DOIUrl":"10.1016/j.exphem.2026.105521","url":null,"abstract":"&lt;div&gt;&lt;div&gt;Although single-cell transcriptomics has revealed rich heterogeneity in hematopoietic stem cell (HSC) biology, most analyses remain descriptive, capturing static states rather than dynamic processes. In this presentation, I discussed recent efforts to move from static atlases toward quantitative models of cell flux during early differentiation.&lt;/div&gt;&lt;div&gt;Using time-resolved single-cell RNA sequencing (RNA-seq) from native mouse bone marrow, we developed a deep learning framework to reconstruct differentiation dynamics within transcriptional state space. Building on our &lt;em&gt;Pseudodynamics+&lt;/em&gt; preprint, this approach infers cell-specific flux parameters, enabling quantitative analysis of how individual cells move through early trajectories in vivo.&lt;/div&gt;&lt;div&gt;I also presented complementary studies using ex vivo HSC expansion in polyvinyl alcohol (PVA) culture. Here, longitudinal single-cell profiling combined with clonal tracking allows direct observation of how individual clones navigate differentiation landscapes over time, revealing substantial heterogeneity in clonal persistence, expansion, and lineage progression dynamics obscured by population-level measurements.&lt;/div&gt;&lt;div&gt;Together, these studies highlighted how integrating time-series genomics, clonal analysis, and machine learning provides a dynamic view of HSC biology. Rather than focusing on discrete identities, this framework emphasizes the quantitative rules governing cellular movement through developmental space, establishing a baseline for understanding disease states where differentiation is distorted and offering new opportunities to target pathologic behaviors.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;Although single-cell transcriptomics has revealed rich heterogeneity in hematopoietic stem cell (HSC) biology, most analyses remain descriptive, capturing static states rather than dynamic processes. In this presentation, I discussed recent efforts to move from static atlases toward quantitative models of cell flux during early differentiation.&lt;/div&gt;&lt;div&gt;Using time-resolved single-cell RNA sequencing (RNA-seq) from native mouse bone marrow, we developed a deep learning framework to reconstruct differentiation dynamics within transcriptional state space. Building on our &lt;em&gt;Pseudodynamics+&lt;/em&gt; preprint, this approach infers cell-specific flux parameters, enabling quantitative analysis of how individual cells move through early trajectories in vivo.&lt;/div&gt;&lt;div&gt;I also presented complementary studies using ex vivo HSC expansion in polyvinyl alcohol (PVA) culture. Here, longitudinal single-cell profiling combined with clonal tracking allows direct observation of how individual clones navigate differentiation landscapes over time, revealing substantial heterogeneity in clonal persistence, expansion, and lineage progression dynamics obscured by population-level measurements.&lt;/div&gt;&lt;div&gt;Together, these studies highlighted how integrating time-series genomics, clonal analysis, and machine learning provides a","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"162 ","pages":"Article 105521"},"PeriodicalIF":2.7,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149233830","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":"2022 – EMBRYONIC LYMPHOCYTES CONTRIBUTE TO A GENETIC FORM OF AUTOIMMUNE INFLAMMATION","authors":"Sara Cascione,&nbsp;Elena Morganti,&nbsp;Cristiana Barone,&nbsp;Carlotta Tacconi,&nbsp;Bianca Nesti,&nbsp;Luigi Notarangelo,&nbsp;Anna Villa,&nbsp;Marco De Giovanni,&nbsp;Azzoni Emanuele,&nbsp;Andrea Ditadi","doi":"10.1016/j.exphem.2026.105550","DOIUrl":"10.1016/j.exphem.2026.105550","url":null,"abstract":"&lt;div&gt;&lt;div&gt;The pathophysiology of autoimmunity remains poorly understood, limiting the development of targeted therapies. Omenn Syndrome (OS) is a rare hematological disorder caused by hypomorphic mutations in genes regulating B-/T cell receptor (TCR) rearrangement, leading to impaired lymphocyte development and immunodeficiency. Despite this, a limited number of self-reactive T cell clones expand in peripheral tissues and drive autoimmune manifestations. Notably, residual OS lymphocytes display features of embryonic lymphocytes that arise independently of hematopoietic stem cells (HSCs). We therefore hypothesized that autoreactive T cells in OS may originate from an HSC independent developmental program. Using the Rag2R229Q/R229Q mouse model, we show that embryonic but not adult hematopoietic progenitors generate T cells in vitro. Lineage tracing confirmed the presence of activated embryonic OS lymphocytes in sites displaying autoimmune manifestations. T lymphopoiesis can be restored in adult OS progenitors through LIN28 mediated reprogramming to an embryonic-like state. Stage-specific inhibition of ATM and MIRIN also rescues T cell potential in adult OS cells, suggesting different sensitivity to DNA damage during TCR rearrangement between embryonic and adult T cells. Remarkably, when transplanted into immunodeficient mice, embryonic-like OS progenitors induce intestinal inflammation and tissue alterations, recapitulating OS phenotype. Finally, modeling OS using human induced pluripotent stem cells (iPSC) revealed a conserved developmental resilience of embryonic progenitors to hypomorphic RAG2 mutations, in contrast to the impaired lymphopoiesis of iPSC-derived HSCs. These findings uncover a previously unrecognized contribution of embryonic progenitors to autoreactive T cells and provide a platform to study autoimmune disease and develop targeted therapies.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;The pathophysiology of autoimmunity remains poorly understood, limiting the development of targeted therapies. Omenn Syndrome (OS) is a rare hematological disorder caused by hypomorphic mutations in genes regulating B-/T cell receptor (TCR) rearrangement, leading to impaired lymphocyte development and immunodeficiency. Despite this, a limited number of self-reactive T cell clones expand in peripheral tissues and drive autoimmune manifestations. Notably, residual OS lymphocytes display features of embryonic lymphocytes that arise independently of hematopoietic stem cells (HSCs). We therefore hypothesized that autoreactive T cells in OS may originate from an HSC independent developmental program. Using the Rag2R229Q/R229Q mouse model, we show that embryonic but not adult hematopoietic progenitors generate T cells in vitro. Lineage tracing confirmed the presence of activated embryonic OS lymphocytes in sites displaying autoimmune manifestations. T lymphopoiesis can be restored in adult OS progenitors through LIN28 mediated reprogramming to an embryonic-like state. Stage-specific ","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"162 ","pages":"Article 105550"},"PeriodicalIF":2.7,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149233965","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":"2038 – A NEW DOUBLE REPORTER STRATEGY REVEALS A SUBSET OF NONMIGRATORY HEMATOPOIETIC STEM CELLS LOCATED IN A DYNAMIC BONE MARROW NICHE","authors":"Tiago C. Luis,&nbsp;Marine Secchi,&nbsp;Cera Mai,&nbsp;Qi Liu,&nbsp;Aya Elmeligy,&nbsp;Sara Gonzalez Anton,&nbsp;Aisha Jibril,&nbsp;Thorsten Richter,&nbsp;Jiarui Xu,&nbsp;Donal Carroll,&nbsp;Nicola Wilson,&nbsp;Konstantinos Kokkaliaris,&nbsp;Kamil Kranc,&nbsp;Berthold Gottgens,&nbsp;Cristina Lo Celso,&nbsp;Tiago Luis","doi":"10.1016/j.exphem.2026.105566","DOIUrl":"10.1016/j.exphem.2026.105566","url":null,"abstract":"&lt;div&gt;&lt;div&gt;Interactions of hematopoietic stem cells (HSCs) with the bone marrow microenvironment are critical to regulate stem cell function in homeostasis, emergency hematopoiesis and aging. The dynamic behavior of endogenous HSCs in their niches has been challenging to study due to the complexity of markers required to define pure HSCs. Multiple recently developed reporter strategies advanced our capacity to identify HSCs in situ. Yet, they provide different levels of HSC enrichment and are frequently not stable in situations of perturbed hematopoiesis, leading to contradictory observations of HSC localization and migratory behavior. Here, we employed a new double reporter strategy by combining the Hoxb5-mKO2 and Vwf-GFP reporters that are stably expressed in homeostasis, stress, and aging. Hoxb5&lt;sup&gt;+&lt;/sup&gt;Vwf&lt;sup&gt;+&lt;/sup&gt; cells represent a subset of highly pure and potent long-term HSCs with a platelet-biased pattern of differentiation that are included in the populations identified by other reporter strategies. Intravital microscopy revealed Hoxb5&lt;sup&gt;+&lt;/sup&gt;Vwf&lt;sup&gt;+&lt;/sup&gt; cells to be nonmigratory in homeostasis, aging, or following platelet depletion when these cells are actively proliferating, indicating that this nonmigratory behavior is independent of cell cycle status. We found Hoxb5&lt;sup&gt;+&lt;/sup&gt;Vwf&lt;sup&gt;+&lt;/sup&gt; HSCs in perivascular niches with a higher coverage by LepR&lt;sup&gt;+&lt;/sup&gt; mesenchymal cells but not preferentially located closer to megakaryocytes, when compared with Hoxb5&lt;sup&gt;+&lt;/sup&gt;Vwf&lt;sup&gt;–&lt;/sup&gt; cells. Nevertheless, increased megakaryopoiesis following platelet depletion brings megakaryocytes into close proximity of Hoxb5&lt;sup&gt;+&lt;/sup&gt;Vwf&lt;sup&gt;+&lt;/sup&gt; HSCs, revealing previously unrecognized niche dynamics in HSC regulation during regeneration.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;Interactions of hematopoietic stem cells (HSCs) with the bone marrow microenvironment are critical to regulate stem cell function in homeostasis, emergency hematopoiesis and aging. The dynamic behavior of endogenous HSCs in their niches has been challenging to study due to the complexity of markers required to define pure HSCs. Multiple recently developed reporter strategies advanced our capacity to identify HSCs in situ. Yet, they provide different levels of HSC enrichment and are frequently not stable in situations of perturbed hematopoiesis, leading to contradictory observations of HSC localization and migratory behavior. Here, we employed a new double reporter strategy by combining the Hoxb5-mKO2 and Vwf-GFP reporters that are stably expressed in homeostasis, stress, and aging. Hoxb5&lt;sup&gt;+&lt;/sup&gt;Vwf&lt;sup&gt;+&lt;/sup&gt; cells represent a subset of highly pure and potent long-term HSCs with a platelet-biased pattern of differentiation that are included in the populations identified by other reporter strategies. Intravital microscopy revealed Hoxb5&lt;sup&gt;+&lt;/sup&gt;Vwf&lt;sup&gt;+&lt;/sup&gt; cells to be nonmigratory in homeostasis, aging, or following platelet depletion when these cells are actively p","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"162 ","pages":"Article 105566"},"PeriodicalIF":2.7,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149233967","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}