Experimental hematology最新文献

{"title":"2044 – DIVERGENT MITOCHONDRIAL PROGRAMMING OF HEMATOPOIETIC STEM CELL FUNCTION BY MATERNAL FOLATE STATUS","authors":"Brian Krum, Ava Niaza, Victoria Chiou, Robert Welner, Brittany Curtiss, Alana Franceski, Sajesan Aryal, Anton Classen, Fanny Zhou, Travis Nemkov, Angelo D'Alessandro, Rui Lu, Robert Signer, Martha Field, Anna Beaudin","doi":"10.1016/j.exphem.2026.105572","DOIUrl":"10.1016/j.exphem.2026.105572","url":null,"abstract":"<div><div>Hematopoietic stem cells (HSCs) arise during development and generate all blood and immune cells across the lifespan. Maternal nutrition influences developing organ systems, yet the mechanisms by which maternal metabolism programs HSC fitness remain poorly defined. Folate, a central regulator of one-carbon metabolism, links nucleotide synthesis, cellular methylation, redox balance, and mitochondrial function, suggesting it may be a key regulator of HSC developmental programming. Here, we show that maternal folate status alters HSC function through divergent mitochondrial effects. In a dietary model of perinatal folate deficiency or supplementation, offspring exhibited altered adult hematopoiesis. Functionally, folate deficiency compromises HSC regenerative capacity, resulting in poor engraftment and loss of self-renewal, whereas folate supplementation enhances long-term self-renewal with increased fitness revealed upon serial transplantation. These phenotypes arise from opposing mitochondrial programs. Folate deficiency induces persistent metabolic dysfunction, loss of mitochondrial integrity, and structural disruption of cristae, linked to suppression of mitochondrial fusion pathways. In contrast, folate supplementation preserves metabolic homeostasis although enhancing mitochondrial quality control through enhanced autophagy and organelle remodeling, alongside activation of cytoskeletal polarity networks including CDC42 signaling. These findings establish maternal folate availability as a developmental regulator of long-term HSC fitness and identify mitochondrial state as a central mechanism linking prenatal nutrition to lifelong hematopoietic function.</div></div><div>Hematopoietic stem cells (HSCs) arise during development and generate all blood and immune cells across the lifespan. Maternal nutrition influences developing organ systems, yet the mechanisms by which maternal metabolism programs HSC fitness remain poorly defined. Folate, a central regulator of one-carbon metabolism, links nucleotide synthesis, cellular methylation, redox balance, and mitochondrial function, suggesting it may be a key regulator of HSC developmental programming. Here, we show that maternal folate status alters HSC function through divergent mitochondrial effects. In a dietary model of perinatal folate deficiency or supplementation, offspring exhibited altered adult hematopoiesis. Functionally, folate deficiency compromises HSC regenerative capacity, resulting in poor engraftment and loss of self-renewal, whereas folate supplementation enhances long-term self-renewal with increased fitness revealed upon serial transplantation. These phenotypes arise from opposing mitochondrial programs. Folate deficiency induces persistent metabolic dysfunction, loss of mitochondrial integrity, and structural disruption of cristae, linked to suppression of mitochondrial fusion pathways. In contrast, folate supplementation preserves metabolic homeostasis although enhancin","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"162 ","pages":"Article 105572"},"PeriodicalIF":2.7,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149234122","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":"1016 – MHC II-DRIVEN IMMUNITY IN MALIGNANT HEMATOPOIETIC STEM AND PROGENITOR CELLS","authors":"Wei Tong,&nbsp;Ruoxing Wang,&nbsp;Mohammed Alhusayan,&nbsp;Eric Wafula,&nbsp;Bowen Xing,&nbsp;Emma Hedgepeth,&nbsp;Kaosheng Lv,&nbsp;Alexander Perl,&nbsp;Yan Liu,&nbsp;Hamid Band,&nbsp;Lawrence Eisenlohr,&nbsp;Junwei Shi,&nbsp;Irfan Asangani","doi":"10.1016/j.exphem.2026.105512","DOIUrl":"10.1016/j.exphem.2026.105512","url":null,"abstract":"<div><div>Hematopoietic stem and progenitor cells (HSPCs) express major histocompatibility complex class II (MHC II or human leukocyte antigen, HLA-II) to enable immune surveillance. Reduced MHC II expression in acute myeloid leukemia (AML) is strongly associated with immune escape and relapse following allogeneic stem cell transplantation, yet the mechanisms regulating MHC II in HSPCs or AML are poorly established. Here, we identified Casitas B-lineage lymphoma (CBL) family E3 ubiquitin ligases—frequently mutated in various myeloid malignancies—as critical regulators of MHC II in both normal and malignant HSPCs. Genetic loss or mutation of <em>CBL</em> markedly reduces MHC II expression in stem-like AML cells and in HSPCs from <em>Cbl/Cblb</em>-deficient mice, impairing antigen presentation. Mechanistically, <em>CBL</em> inactivation downregulates the ETS-related gene (ERG), a heptad transcription factor essential for normal and leukemic stem cells. ERG binds to a previously unrecognized HSPC-specific class II MHC transactivator (CIITA) enhancer to sustain MHC II expression. Consistent with this mechanism, stem-like blasts from <em>CBL</em>-mutant primary AMLs and juvenile myelomonocytic leukemias (JMMLs) exhibit diminished MHC II expression. These findings uncover an HSPC-specific ERG-CIITA-MHC II regulatory axis linking oncogenic signaling to immune evasion, highlighting a potential therapeutic strategy to restore immune surveillance.</div></div><div>Hematopoietic stem and progenitor cells (HSPCs) express major histocompatibility complex class II (MHC II or human leukocyte antigen, HLA-II) to enable immune surveillance. Reduced MHC II expression in acute myeloid leukemia (AML) is strongly associated with immune escape and relapse following allogeneic stem cell transplantation, yet the mechanisms regulating MHC II in HSPCs or AML are poorly established. Here, we identified Casitas B-lineage lymphoma (CBL) family E3 ubiquitin ligases—frequently mutated in various myeloid malignancies—as critical regulators of MHC II in both normal and malignant HSPCs. Genetic loss or mutation of <em>CBL</em> markedly reduces MHC II expression in stem-like AML cells and in HSPCs from <em>Cbl/Cblb</em>-deficient mice, impairing antigen presentation. Mechanistically, <em>CBL</em> inactivation downregulates the ETS-related gene (ERG), a heptad transcription factor essential for normal and leukemic stem cells. ERG binds to a previously unrecognized HSPC-specific class II MHC transactivator (CIITA) enhancer to sustain MHC II expression. Consistent with this mechanism, stem-like blasts from <em>CBL</em>-mutant primary AMLs and juvenile myelomonocytic leukemias (JMMLs) exhibit diminished MHC II expression. These findings uncover an HSPC-specific ERG-CIITA-MHC II regulatory axis linking oncogenic signaling to immune evasion, highlighting a potential therapeutic strategy to restore immune surveillance.</div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"162 ","pages":"Article 105512"},"PeriodicalIF":2.7,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149234151","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":"1020 – BONE MARROW MICROENVIRONMENT IN NORMAL AND LEUKEMIC B-CELL DEVELOPMENT: FRIEND OR FOE?","authors":"Stéphane Mancini","doi":"10.1016/j.exphem.2026.105515","DOIUrl":"10.1016/j.exphem.2026.105515","url":null,"abstract":"&lt;div&gt;&lt;div&gt;Bone marrow mesenchymal stromal cells and endothelial cells play an essential role in hematopoietic stem cell (HSC) maintenance but also in the differentiation of committed hematopoietic cells through direct contact and the secretion of specific factors. Numerous studies have examined the impact of chemokine (C-X-C motif) ligand 12 (CXCL12) and stem cell factor (SCF), which are produced by periarteriolar and perisinusoidal niches, on HSC function. Hematopoietic malignancies also exploit protective niche signals that contribute to treatment resistance. Despite advances in reporter models and single-cell transcriptomics that have led to significant progress in understanding niche heterogeneity and plasticity, the networks that govern niche specificity and the influence of niche factors on leukemogenesis and resistance to treatment remain poorly understood.&lt;/div&gt;&lt;div&gt;In the laboratory, we are interested in niches that are specific to differentiating B cells and their malignant counterpart, B-cell acute lymphoblastic leukemia (B-ALL). Pro-B cells, in which immunoglobulin heavy (IgH) chain gene rearrangements are initiated, are controlled by CXCL12 and interleukin (IL)-7. We observed that IL-7 is produced by a perisinusoidal stromal (PSS) cell population, and pro-B cells are located in contact with these cells. PSS cells also express CXCL12 and SCF and thus compose the perisinusoidal niche that can sustain both HSC maintenance and early B-cell differentiation simultaneously. At the next pre-B-cell stage, the IgH chain associates with the surrogate light chain to form the pre-B-cell receptor (pre-BCR). We found that galectin-1 (GAL1), the pre-BCR ligand, is secreted by bone marrow stromal cells, which are distinct from PSS cells, and contributes to pre-BCR-dependent proliferation. Pre-B cells were found in close proximity to GAL1-expressing stromal cells in the bone marrow. Finally, we applied our findings to pathology and observed that GAL1, when expressed by normal stromal cell niches, can influence leukemogenesis, the fate of leukemic cells, and their resistance to treatment. These results pave the way for new therapeutic strategies that target interactions between leukemic cells and their microenvironment.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;Bone marrow mesenchymal stromal cells and endothelial cells play an essential role in hematopoietic stem cell (HSC) maintenance but also in the differentiation of committed hematopoietic cells through direct contact and the secretion of specific factors. Numerous studies have examined the impact of chemokine (C-X-C motif) ligand 12 (CXCL12) and stem cell factor (SCF), which are produced by periarteriolar and perisinusoidal niches, on HSC function. Hematopoietic malignancies also exploit protective niche signals that contribute to treatment resistance. Despite advances in reporter models and single-cell transcriptomics that have led to significant progress in understanding niche heterogeneity and plasticity, the networks ","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"162 ","pages":"Article 105515"},"PeriodicalIF":2.7,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149234152","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":"2016 – ARCHITECTURE OF THE TPO-MPL SIGNALING COMPLEX: DEFINING THE ROLE OF CRM2 IN RECEPTOR SCAFFOLDING AND ALLOSTERIC CONTROL","authors":"Lizzy Morritt,&nbsp;Matt Tyreman,&nbsp;Agnes Noy,&nbsp;David Kent,&nbsp;Ian Hitchcock","doi":"10.1016/j.exphem.2026.105544","DOIUrl":"10.1016/j.exphem.2026.105544","url":null,"abstract":"&lt;div&gt;&lt;div&gt;The thrombopoietin (TPO)–thrombopoietin receptor (MPL) complex is critical for hematopoietic stem cell maintenance and megakaryocyte differentiation. Mutations in this pathway produce contrasting diseases: loss-of-function variants cause thrombocytopenia and can lead to bone marrow failure, although activating changes drive myeloid malignancies. By solving the TPO–2 × MPL structure, we identified how the two distinct cytokine receptor modules (CRM1 and CRM2) interact and control active geometry of the ligand-receptor complex. CRM1 directly interacts with TPO, allowing for dimerization of two MPL monomers. The role of CRM2 however is less clear and appears to have key roles in receptor scaffolding and intermonomer geometry, possibly setting the orientation of the transmembrane and intracellular domains. To define CRM2’s role, we purified the isolated CRM2 domain and used it alongside the full extracellular MPL domain in phage display selections to discover CRM2-binding ligands, then tested their recognition on the intact receptor. Molecular dynamics simulations showed how clinical and engineered mutations reshape MPL geometry and disrupt CRM2-mediated contacts. Together, biochemical and computational data demonstrate that CRM2 governs receptor architecture and is a tractable target for allosteric modulation. CRM2-directed ligands therefore offer a promising route to restore or restrain MPL signaling in disorders ranging from thrombocytopenia to myeloproliferative disease.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;The thrombopoietin (TPO)–thrombopoietin receptor (MPL) complex is critical for hematopoietic stem cell maintenance and megakaryocyte differentiation. Mutations in this pathway produce contrasting diseases: loss-of-function variants cause thrombocytopenia and can lead to bone marrow failure, although activating changes drive myeloid malignancies. By solving the TPO–2 × MPL structure, we identified how the two distinct cytokine receptor modules (CRM1 and CRM2) interact and control active geometry of the ligand-receptor complex. CRM1 directly interacts with TPO, allowing for dimerization of two MPL monomers. The role of CRM2 however is less clear and appears to have key roles in receptor scaffolding and intermonomer geometry, possibly setting the orientation of the transmembrane and intracellular domains. To define CRM2’s role, we purified the isolated CRM2 domain and used it alongside the full extracellular MPL domain in phage display selections to discover CRM2-binding ligands, then tested their recognition on the intact receptor. Molecular dynamics simulations showed how clinical and engineered mutations reshape MPL geometry and disrupt CRM2-mediated contacts. Together, biochemical and computational data demonstrate that CRM2 governs receptor architecture and is a tractable target for allosteric modulation. CRM2-directed ligands therefore offer a promising route to restore or restrain MPL signaling in disorders ranging from thrombocytopenia to myeloproli","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"162 ","pages":"Article 105544"},"PeriodicalIF":2.7,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149234159","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(26)00542-4","DOIUrl":"10.1016/S0301-472X(26)00542-4","url":null,"abstract":"","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"162 ","pages":"Article 105909"},"PeriodicalIF":2.7,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149155032","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}

{"title":"1009 – BAD ALLIES: COEXISTING MUTANT CLONES REWIRE THE MARROW MICROENVIRONMENT TO PROMOTE EXPANSION","authors":"Rob Welner,&nbsp;Alana Franceski,&nbsp;Caroline Ennis,&nbsp;Daniel Phillips,&nbsp;Paran Goel","doi":"10.1016/j.exphem.2026.105505","DOIUrl":"10.1016/j.exphem.2026.105505","url":null,"abstract":"&lt;div&gt;&lt;div&gt;The progression of clonal hematopoiesis (CH) is shaped not only by cell-intrinsic mutational effects but also by cooperative signaling interactions among coexisting mutant clones that collectively remodel the bone marrow niche, alter cytokine landscapes, and reshape competitive fitness hierarchies in ways that fundamentally influence disease trajectory. Although clone size predicts clinical risk and &lt;em&gt;DNMT3A&lt;/em&gt; and &lt;em&gt;TET2&lt;/em&gt; mutations account for the majority of CH cases, the mechanisms by which coexisting clones interact to drive expansion remain poorly defined. Through the development of nonirradiated competitive transplant chimeras incorporating &lt;em&gt;Dnmt3a&lt;/em&gt;-mutant and &lt;em&gt;Tet2&lt;/em&gt;-deficient bone marrow under homeostatic conditions, introduced individually and in combination, three interconnected findings were identified: &lt;em&gt;Dnmt3a&lt;/em&gt;-mutant clones exhibit modest, lineage-neutral expansion in isolation; &lt;em&gt;Tet2&lt;/em&gt;-deficient clones expand robustly and promote myeloid output without increasing HSC frequency; and coexistence of both populations accelerates &lt;em&gt;Dnmt3a&lt;/em&gt;-mutant clone expansion and induces distinct stem and myeloid phenotypes not observed when either clone competes alone. Mechanistically, single-cell transcriptomic analyses and bulk chromatin accessibility profiling reveal mutation-specific remodeling of cytokine-responsive transcriptional states and pathways governing stem cell persistence, consistent with &lt;em&gt;Tet2&lt;/em&gt;-mutant cells reshaping the local signaling environment to lower response thresholds and potentiate expansion programs in neighboring &lt;em&gt;Dnmt3a&lt;/em&gt;-mutant populations. These findings are being extended through analysis of multi-mutation CH cohorts to define how clonal composition influences inflammatory signaling and disease progression in human disease. It is proposed that CH evolution is governed less by the presence of individual mutations than by cooperative, niche-mediated crosstalk among coexisting clones, thereby establishing a framework in which clonal competition drives CH progression and identifying shared signaling dependencies as candidate targets to limit expansion and reduce transformation risk.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;The progression of clonal hematopoiesis (CH) is shaped not only by cell-intrinsic mutational effects but also by cooperative signaling interactions among coexisting mutant clones that collectively remodel the bone marrow niche, alter cytokine landscapes, and reshape competitive fitness hierarchies in ways that fundamentally influence disease trajectory. Although clone size predicts clinical risk and &lt;em&gt;DNMT3A&lt;/em&gt; and &lt;em&gt;TET2&lt;/em&gt; mutations account for the majority of CH cases, the mechanisms by which coexisting clones interact to drive expansion remain poorly defined. Through the development of nonirradiated competitive transplant chimeras incorporating &lt;em&gt;Dnmt3a&lt;/em&gt;-mutant and &lt;em&gt;Tet2&lt;/em&gt;-deficient bone marrow under homeostatic conditions, introduced indiv","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"162 ","pages":"Article 105505"},"PeriodicalIF":2.7,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149233603","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":"2013 – IN VIVO CRISPR/CAS9-MEDIATED MODELING OF CLONAL HEMATOPOIESIS VIA A MULTI-LOX HYDRA ALLELE","authors":"Amanda Jimenez-Pompa,&nbsp;Raúl Sánchez Lanzas,&nbsp;Peter Hall,&nbsp;Patrick Connelly,&nbsp;Shondra Miller,&nbsp;Miguel Ganuza","doi":"10.1016/j.exphem.2026.105541","DOIUrl":"10.1016/j.exphem.2026.105541","url":null,"abstract":"&lt;div&gt;&lt;div&gt;Clonal hematopoiesis (CH) is an age-associated process driven by somatic mutations in hematopoietic stem and progenitor cells, linked to increased risk of hematological malignancies and cardiovascular disease. Despite its clinical relevance, its study remains limited by the lack of physiologically relevant in vivo models capturing its genetic complexity. Most studies rely on transplantation approaches, although available genetic models carry only up to three mutations, failing to recapitulate the mutational landscape observed in human CH.&lt;/div&gt;&lt;div&gt;To address this, we engineered the Hydra mouse model, a hematopoietic-specific, inducible system based on four synthetic alleles, including a modular multi-lox allele combined with CRISPR/Cas9-mediated mutagenesis. This design enables the in vivo generation of hematopoietic clones carrying random combinations of up to 10 recurrent CH-associated mutations: Dnmt3a, Tet2, Cbl, Asxl1, Ppm1d, Sf3b1, Atm, Bcor, Rad21, and Trp53. Remarkably, Hydra allows the in vivo study of clonal competition during native hematopoiesis.&lt;/div&gt;&lt;div&gt;Targeted next-generation sequencing of approximately 1700 colonies from Hydra mice revealed mutations across target genes at ∼0.2% frequency at early time points. Aged cohorts (12 months) showed higher variant allele frequencies, consistent with clonal expansion, with individuals carrying mutations in up to four genes (normally 1–2), closely recapitulating human CH.&lt;/div&gt;&lt;div&gt;Exposure to acute and chronic inflammatory stress revealed expansion of Dnmt3a and Tet2 mutant clones. Acute inflammation yielded enlarged Asxl1 mutant clones, whereas chronic inflammation selected for Atm and Bcor mutations, indicating gene-specific responses to environmental stress.&lt;/div&gt;&lt;div&gt;Overall, these results establish Hydra as a comprehensive in vivo CH model that closely recapitulates human CH enabling the study of clonal dynamics in an unbiased setting.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;Clonal hematopoiesis (CH) is an age-associated process driven by somatic mutations in hematopoietic stem and progenitor cells, linked to increased risk of hematological malignancies and cardiovascular disease. Despite its clinical relevance, its study remains limited by the lack of physiologically relevant in vivo models capturing its genetic complexity. Most studies rely on transplantation approaches, although available genetic models carry only up to three mutations, failing to recapitulate the mutational landscape observed in human CH.&lt;/div&gt;&lt;div&gt;To address this, we engineered the Hydra mouse model, a hematopoietic-specific, inducible system based on four synthetic alleles, including a modular multi-lox allele combined with CRISPR/Cas9-mediated mutagenesis. This design enables the in vivo generation of hematopoietic clones carrying random combinations of up to 10 recurrent CH-associated mutations: Dnmt3a, Tet2, Cbl, Asxl1, Ppm1d, Sf3b1, Atm, Bcor, Rad21, and Trp53. Remarkably, Hydra allows the in vivo study of clonal compe","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"162 ","pages":"Article 105541"},"PeriodicalIF":2.7,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149233749","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":"1003 – EIF4E DRIVES AML CELL COLONIZATION OF THE BONE MARROW NICHE: INSIGHTS FROM A 3D MESENCHYMAL SPHEROID CO-CULTURE MODEL","authors":"Monica Guzman","doi":"10.1016/j.exphem.2026.105499","DOIUrl":"10.1016/j.exphem.2026.105499","url":null,"abstract":"<div><div>The crosstalk between acute myeloid leukemia (AML) cells and the bone marrow niche is crucial for disease progression. Modeling AML-niche interactions is key because these interactions support survival, chemotherapy resistance, and disease maintenance, and the niche serves as a specialized microenvironment for leukemia stem cells.</div><div>We have implemented a three-dimensional (3D) in vitro model that mimics the leukemic bone marrow niche, particularly the interaction between AML cells and mesenchymal stromal cells (MSCs). This model consists of a spheroid formed from bone marrow MSCs without synthetic scaffolds or exogenous materials. AML cells are cocultured with the spheroid to assess their colonization capacity.</div><div>Using this model, we identified a new role for eukaryotic translation initiation factor 4E (eIF4E) in adhesion and colonization, as demonstrated through genetic and pharmacologic depletion of eIF4E. These findings were also validated in vivo.</div></div><div>The crosstalk between acute myeloid leukemia (AML) cells and the bone marrow niche is crucial for disease progression. Modeling AML-niche interactions is key because these interactions support survival, chemotherapy resistance, and disease maintenance, and the niche serves as a specialized microenvironment for leukemia stem cells.</div><div>We have implemented a three-dimensional (3D) in vitro model that mimics the leukemic bone marrow niche, particularly the interaction between AML cells and mesenchymal stromal cells (MSCs). This model consists of a spheroid formed from bone marrow MSCs without synthetic scaffolds or exogenous materials. AML cells are cocultured with the spheroid to assess their colonization capacity.</div><div>Using this model, we identified a new role for eukaryotic translation initiation factor 4E (eIF4E) in adhesion and colonization, as demonstrated through genetic and pharmacologic depletion of eIF4E. These findings were also validated in vivo.</div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"162 ","pages":"Article 105499"},"PeriodicalIF":2.7,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149233757","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":"1002 – THINKING FAST AND SLOW: ORIGINS AND CONSEQUENCES OF STEM CELL BIASES","authors":"Alejo Rodriguez-Fraticelli,&nbsp;Marta Lopez-Osias,&nbsp;Elvira Gonzalez-Saiz,&nbsp;Indranil Singh,&nbsp;Andrea Polazzi,&nbsp;Daniel Fernandez-Perez,&nbsp;Robert Bowman","doi":"10.1016/j.exphem.2026.105498","DOIUrl":"10.1016/j.exphem.2026.105498","url":null,"abstract":"&lt;div&gt;&lt;div&gt;A central challenge in regenerative medicine is understanding how individual stem cells transition from multipotency to biased functional states. By integrating high-resolution single-cell lineage tracing with innovative culture systems, we demonstrated that both healthy hematopoietic stem cells (HSCs) and leukemia stem cells (LSCs) utilize stable, heritable programs to govern their fate.&lt;/div&gt;&lt;div&gt;Our study of healthy hematopoiesis reveals that adult HSC heterogeneity is architected during a narrow postnatal window. We identified a transient, neonatal HSC state induced by stress activation and marked by &lt;em&gt;Tppp3&lt;/em&gt; expression. These “neonatal-stress” cells serve as a primary source of adult platelet-biased HSCs. Crucially, this program is mammalian target of rapamycin (mTOR)-dependent; transient rapamycin treatment during the first postnatal week effectively erases this stress memory, shifting the adult repertoire toward fetal-like multilineage fates. This suggests that neonatal-stress diversifies stem cell functional biases and can permanently imprint clonal diversity.&lt;/div&gt;&lt;div&gt;Paralleling this developmental logic in malignant hematopoiesis, we investigated LSC clonality using the nucleophosmin 1 cytoplasmic-mutated (Npm1c)A FMS-like tyrosine kinase 3-internal tandem duplication (Flt3-ITD) model. To maintain and expand LSCs ex vivo&lt;em&gt;,&lt;/em&gt; we developed polymer-based leukemic stem cell cultures (PLSTCs). Remarkably, this platform achieves a 1,000-fold enrichment of functional LSCs, allowing us to map the heritable transcriptional states that drive chemoresistance. We found that treatment-resistant LSC clones are primed by a rare high-plasticity cell state that undergoes a fate switch toward megakaryocytic-erythroid-like lineages. Through clustered regularly interspaced short palindromic repeats (CRISPR) droplet sequencing (CROPseq) screening, we identified chondroitin-sulfate synthesis as a key metabolic requirement for maintaining these primitive, resistant states.&lt;/div&gt;&lt;div&gt;Together, these findings revealed that stem cell “memory,” triggered by physiological postnatal stress or oncogenic plasticity, drives long-term clonal heterogeneity, offering new therapeutic windows to intercept biased hematopoiesis and leukemic relapse.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;A central challenge in regenerative medicine is understanding how individual stem cells transition from multipotency to biased functional states. By integrating high-resolution single-cell lineage tracing with innovative culture systems, we demonstrated that both healthy hematopoietic stem cells (HSCs) and leukemia stem cells (LSCs) utilize stable, heritable programs to govern their fate.&lt;/div&gt;&lt;div&gt;Our study of healthy hematopoiesis reveals that adult HSC heterogeneity is architected during a narrow postnatal window. We identified a transient, neonatal HSC state induced by stress activation and marked by &lt;em&gt;Tppp3&lt;/em&gt; expression. These “neonatal-stress” cells serve as a primary source of ad","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"162 ","pages":"Article 105498"},"PeriodicalIF":2.7,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149233758","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":"2020 – A CONSERVED TRANSCRIPTIONAL PROGRAM DICTATES THE ENGRAFTMENT OF EX VIVO EXPANDED HSCS","authors":"Ali Motazedian,&nbsp;Phillip Nguyen,&nbsp;Elanor Wainwright,&nbsp;Enid Lam,&nbsp;Mark Dawson","doi":"10.1016/j.exphem.2026.105548","DOIUrl":"10.1016/j.exphem.2026.105548","url":null,"abstract":"&lt;div&gt;&lt;div&gt;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.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;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}