Pub Date : 2025-11-01DOI: 10.1016/j.exphem.2025.104939
Isabel Beerman , Le Zong , Bongsoo Park , Yaqiang Cao , Fei Ma , Wakako Kuribayashi , Keji Zhao
Age-associated hematopoietic stem cell (HSC) dysfunction is accompanied by dramatic transcription changes, but it remains unclear whether specific transcripts could orchestrate these HSC aging phenotypes. Here, we performed epigenetic profiling to investigate the regulatory mechanisms underlying the HSC aging transcriptome and screen for potential aging driver genes. We showed that dysregulated 3D chromatin organization, altered histone modifications, and changed chromatin accessibility shape the HSC aging transcriptome. From the compilation of these data, we identified a new looping structure formed between part of the Btaf1 gene and the whole Ide gene in old HSCs (OHSCs), which is accompanied by overexpression of a novel, shorter variant of Btaf1 (nBtaf1). Mechanistically, elevated expression of nBtaf1 drives the aging-associated overexpression of HSC- and megakaryocyte progenitor (MkP)-related genes by regulating TBP binding at their promoters, which contributes to HSC expansion and elevated MkP production in aged mice. ShRNA-mediated knockdown of nBtaf1 restores a younger HSC transcriptome and specifically represses aging-associated HSC expansion and elevated MkP production. In summary, our data provide high-resolution analysis of a dysregulated HSC aging epigenome and reveal a novel Btaf1 variant that drives HSC aging phenotypes in mice.
{"title":"2026 – AGE-ASSOCIATED CHROMATIN REORGANIZATION DRIVES OVEREXPRESSION OF A NOVEL BTAF1 VARIANT REGULATING HSC SELF-RENEWAL AND MKP DIFFERENTIATION","authors":"Isabel Beerman , Le Zong , Bongsoo Park , Yaqiang Cao , Fei Ma , Wakako Kuribayashi , Keji Zhao","doi":"10.1016/j.exphem.2025.104939","DOIUrl":"10.1016/j.exphem.2025.104939","url":null,"abstract":"<div><div>Age-associated hematopoietic stem cell (HSC) dysfunction is accompanied by dramatic transcription changes, but it remains unclear whether specific transcripts could orchestrate these HSC aging phenotypes. Here, we performed epigenetic profiling to investigate the regulatory mechanisms underlying the HSC aging transcriptome and screen for potential aging driver genes. We showed that dysregulated 3D chromatin organization, altered histone modifications, and changed chromatin accessibility shape the HSC aging transcriptome. From the compilation of these data, we identified a new looping structure formed between part of the Btaf1 gene and the whole Ide gene in old HSCs (OHSCs), which is accompanied by overexpression of a novel, shorter variant of Btaf1 (nBtaf1). Mechanistically, elevated expression of nBtaf1 drives the aging-associated overexpression of HSC- and megakaryocyte progenitor (MkP)-related genes by regulating TBP binding at their promoters, which contributes to HSC expansion and elevated MkP production in aged mice. ShRNA-mediated knockdown of nBtaf1 restores a younger HSC transcriptome and specifically represses aging-associated HSC expansion and elevated MkP production. In summary, our data provide high-resolution analysis of a dysregulated HSC aging epigenome and reveal a novel Btaf1 variant that drives HSC aging phenotypes in mice.</div></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"151 ","pages":"Article 104939"},"PeriodicalIF":2.1,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145619921","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}
Pub Date : 2025-11-01DOI: 10.1016/j.exphem.2025.104944
Qinyu Zhang , Anna Konturek-Ciesla , Rasmus Olofzon , Ouyang Yuan , Shabnam Kharazi , David Bryder
Hematopoietic stem cell (HSC) transplantation can cure many blood disorders, but broader clinical use is limited by two key challenges: the scarcity of transplantable HSCs and the toxicity of pretransplant conditioning. To address these issues, we combined recent advances in ex vivo HSC expansion with nongenotoxic transplantation strategies.
Using a defined culture system, we expanded rigorously purified murine HSCs in vitro. After 3 weeks, only ∼0.1% of cultured cells retained the canonical HSC phenotype (Lin−Sca1+cKit+CD150+CD48−/lowEPCRhigh), yet these rare cells accounted for nearly all long-term, multilineage reconstitution activity. Quantitative transplantation assays revealed an approximate 500-fold expansion of functional HSCs, despite extensive differentiation within the cultures. Single-cell multimodal RNA and assay for transposase-accessible chromatin using sequencing (ATAC-seq) profiling revealed divergent self-renewal trajectories, with most progeny supporting only short-term rescue.
To translate these findings in vivo, we tested two nongenotoxic conditioning strategies. Antibody-mediated depletion of host HSCs enabled multilineage engraftment, while transient mobilization followed by transplantation at the mobilization peak also allowed donor cell entry. When combined, these approaches showed strong synergy, enhancing donor engraftment. Further optimization of timing and dose improved long-term hematopoietic output.
Finally, we applied this approach in a murine model of genetically predisposed myelodysplastic syndrome (MDS), a severe, early-onset condition in children. Expanded HSC transplantation delayed disease onset, reduced MDS incidence, and fully prevented transformation to acute leukemia. Together, these findings support a safe and effective platform for HSC-based treatment and prevention of high-risk blood disorders.
{"title":"3004 – IN VITRO EXPANDED HEMATOPOIETIC STEM CELLS COMBINED WITH NON-GENOTOXIC CONDITIONING ENABLE EFFICIENT TRANSPLANTATION AND SUPPRESS MYELOID DISEASE","authors":"Qinyu Zhang , Anna Konturek-Ciesla , Rasmus Olofzon , Ouyang Yuan , Shabnam Kharazi , David Bryder","doi":"10.1016/j.exphem.2025.104944","DOIUrl":"10.1016/j.exphem.2025.104944","url":null,"abstract":"<div><div>Hematopoietic stem cell (HSC) transplantation can cure many blood disorders, but broader clinical use is limited by two key challenges: the scarcity of transplantable HSCs and the toxicity of pretransplant conditioning. To address these issues, we combined recent advances in ex vivo HSC expansion with nongenotoxic transplantation strategies.</div><div>Using a defined culture system, we expanded rigorously purified murine HSCs in vitro. After 3 weeks, only ∼0.1% of cultured cells retained the canonical HSC phenotype (Lin−Sca1+cKit+CD150+CD48−/lowEPCRhigh), yet these rare cells accounted for nearly all long-term, multilineage reconstitution activity. Quantitative transplantation assays revealed an approximate 500-fold expansion of functional HSCs, despite extensive differentiation within the cultures. Single-cell multimodal RNA and assay for transposase-accessible chromatin using sequencing (ATAC-seq) profiling revealed divergent self-renewal trajectories, with most progeny supporting only short-term rescue.</div><div>To translate these findings in vivo, we tested two nongenotoxic conditioning strategies. Antibody-mediated depletion of host HSCs enabled multilineage engraftment, while transient mobilization followed by transplantation at the mobilization peak also allowed donor cell entry. When combined, these approaches showed strong synergy, enhancing donor engraftment. Further optimization of timing and dose improved long-term hematopoietic output.</div><div>Finally, we applied this approach in a murine model of genetically predisposed myelodysplastic syndrome (MDS), a severe, early-onset condition in children. Expanded HSC transplantation delayed disease onset, reduced MDS incidence, and fully prevented transformation to acute leukemia. Together, these findings support a safe and effective platform for HSC-based treatment and prevention of high-risk blood disorders.</div></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"151 ","pages":"Article 104944"},"PeriodicalIF":2.1,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145619933","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}
Pub Date : 2025-11-01DOI: 10.1016/j.exphem.2025.104925
Youqi Wang, Rui QU
Dendritic cells (DCs) are key cellular components of the immune system and perform crucial functions in innate and acquired immunity. In mammals, it is generally believed that DCs originate exclusively from hematopoietic stem cells (HSCs). Using a temporal-spatial resolved fate-mapping system, here we show that, in zebrafish, DCs arise from two sources: dorsal aorta-born endothelium-derived hematopoietic progenitors (EHPs) and HSCs. The EHP-derived DCs emerge early, predominantly colonizing the developing thymus during larval stages and diminishing by juvenile stages. In contrast, HSC-derived DCs emerge later and can populate different tissues from late larval stages to adulthood. We further document that the EHP- and HSC-derived DCs display different dependencies on Fms-like tyrosine kinase 3 (Flt3), a pivotal receptor tyrosine kinase crucial for DC development in mammals. Our study reveals the presence of two distinct waves of DC development in zebrafish, each with unique origins and developmental controls.
{"title":"2012 – DENDRITIC CELLS IN DEVELOPING AND ADULT ZEBRAFISH ARISE FROM DIFFERENT ORIGINS AND DISPLAY DISTINCT FLT3 DEPENDENCIES","authors":"Youqi Wang, Rui QU","doi":"10.1016/j.exphem.2025.104925","DOIUrl":"10.1016/j.exphem.2025.104925","url":null,"abstract":"<div><div>Dendritic cells (DCs) are key cellular components of the immune system and perform crucial functions in innate and acquired immunity. In mammals, it is generally believed that DCs originate exclusively from hematopoietic stem cells (HSCs). Using a temporal-spatial resolved fate-mapping system, here we show that, in zebrafish, DCs arise from two sources: dorsal aorta-born endothelium-derived hematopoietic progenitors (EHPs) and HSCs. The EHP-derived DCs emerge early, predominantly colonizing the developing thymus during larval stages and diminishing by juvenile stages. In contrast, HSC-derived DCs emerge later and can populate different tissues from late larval stages to adulthood. We further document that the EHP- and HSC-derived DCs display different dependencies on Fms-like tyrosine kinase 3 (Flt3), a pivotal receptor tyrosine kinase crucial for DC development in mammals. Our study reveals the presence of two distinct waves of DC development in zebrafish, each with unique origins and developmental controls.</div></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"151 ","pages":"Article 104925"},"PeriodicalIF":2.1,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145620048","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}
Pub Date : 2025-11-01DOI: 10.1016/j.exphem.2025.104912
Ulrich Steidl
Recent work has indicated that considerable subclonal complexity of a heterogeneous pool of stem cells is central to the ability of the hematopoietic system to respond to physiologic challenges, as well as to the pathogenesis and progression of hematologic malignancies. Although substantial efforts have shed light on genetic/mutational heterogeneity, understanding nongenetic mechanisms of stem cell heterogeneity, dynamics, and selection processes is a key scientific challenge with considerable translational implications. Recent studies from our laboratory have uncovered novel sources and mechanisms of stem cell heterogeneity (Gao et al., Science 2024) and pool size regulation (Takeishi et al., Nature 2025) and found that dysregulated transcription is a hallmark of preleukemic stem cells (Will et al., Nat Med 2015; Chen et al., Nat Med 2019; Ueda et al., Cancer Cell 2021). Our work has also revealed an important role of transcriptional noise and plasticity in hematopoietic and leukemic stem cells (Wheat et al., Nature 2020). Newer data also indicate that transcription dynamics and noise are affected by cell-extrinsic leukemia-driving factors such as inflammatory cytokines, which thereby have an effect on stem cell subclonal heterogeneity and dynamics. Furthermore, we have developed novel molecular probes that can be used to target transcription factor (TF) dynamics via pharmacologic TF binding site restriction (Taylor et al., Nat Genet 2024). These studies are leading to novel insights into the mechanisms and dynamics of TF-chromatin interactions in hematopoiesis and leukemia and provide the basis for the development of early intervention strategies and possibly “precision prevention” and “interception” of leukemia pathogenesis and relapse in the future.
最近的研究表明，相当大的亚克隆复杂性是造血系统应对生理挑战的能力的核心，也是血液恶性肿瘤的发病和进展的核心。尽管大量的研究已经揭示了干细胞的遗传/突变异质性，但理解干细胞异质性、动力学和选择过程的非遗传机制是一个具有重大转化意义的关键科学挑战。我们实验室最近的研究发现了干细胞异质性的新来源和机制（Gao等人，Science 2024）和池大小调节（Takeishi等人，Nature 2025），并发现转录失调是白血病前期干细胞的标志（Will等人，Nat Med 2015； Chen等人，Nat Med 2019； Ueda等人，Cancer cell 2021）。我们的工作还揭示了转录噪声和可塑性在造血和白血病干细胞中的重要作用（Wheat等人，Nature 2020）。较新的数据还表明，转录动力学和噪声受到细胞外源性白血病驱动因子（如炎症细胞因子）的影响，从而影响干细胞亚克隆异质性和动力学。此外，我们开发了新型分子探针，可通过药理学上的转录因子结合位点限制来靶向转录因子（TF）动力学（Taylor et al., Nat Genet 2024）。这些研究为造血和白血病中tf -染色质相互作用的机制和动力学提供了新的见解，并为未来白血病发病和复发的早期干预策略和可能的“精确预防”和“拦截”提供了基础。
{"title":"1032 – UNDERSTANDING AND TARGETING STEM CELL HETEROGENEITY IN NORMAL AND MALIGNANT HEMATOPOIESIS","authors":"Ulrich Steidl","doi":"10.1016/j.exphem.2025.104912","DOIUrl":"10.1016/j.exphem.2025.104912","url":null,"abstract":"<div><div>Recent work has indicated that considerable subclonal complexity of a heterogeneous pool of stem cells is central to the ability of the hematopoietic system to respond to physiologic challenges, as well as to the pathogenesis and progression of hematologic malignancies. Although substantial efforts have shed light on genetic/mutational heterogeneity, understanding nongenetic mechanisms of stem cell heterogeneity, dynamics, and selection processes is a key scientific challenge with considerable translational implications. Recent studies from our laboratory have uncovered novel sources and mechanisms of stem cell heterogeneity (Gao et al., Science 2024) and pool size regulation (Takeishi et al., Nature 2025) and found that dysregulated transcription is a hallmark of preleukemic stem cells (Will et al., Nat Med 2015; Chen et al., Nat Med 2019; Ueda et al., Cancer Cell 2021). Our work has also revealed an important role of transcriptional noise and plasticity in hematopoietic and leukemic stem cells (Wheat et al., Nature 2020). Newer data also indicate that transcription dynamics and noise are affected by cell-extrinsic leukemia-driving factors such as inflammatory cytokines, which thereby have an effect on stem cell subclonal heterogeneity and dynamics. Furthermore, we have developed novel molecular probes that can be used to target transcription factor (TF) dynamics via pharmacologic TF binding site restriction (Taylor et al., Nat Genet 2024). These studies are leading to novel insights into the mechanisms and dynamics of TF-chromatin interactions in hematopoiesis and leukemia and provide the basis for the development of early intervention strategies and possibly “precision prevention” and “interception” of leukemia pathogenesis and relapse in the future.</div></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"151 ","pages":"Article 104912"},"PeriodicalIF":2.1,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145620275","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}
Pub Date : 2025-11-01DOI: 10.1016/j.exphem.2025.104982
Yimeng Gao , Xiaojie Hu , Yue Jiang , Renjie Yu , Yirui He , Hua-Bing Li
Hematopoiesis is a tightly regulated process that requires a metabolic switch from glycolysis to mitochondrial respiration. However, the underlying mechanisms remain poorly understood. TRMT10C, a mitochondrial m1A methyltransferase, is highly expressed in hematopoietic stem and progenitor cells. Recent studies have linked missense mutations in TRMT10C to the rare autosomal recessive disorder oxidative phosphorylation deficiency 30, highlighting its clinical relevance. This prompted us to investigate the role of TRMT10C-mediated N1-methylation at position nine of mitochondrial tRNAs in hematopoiesis.
We generated a conditional knockout mouse model (Vav1-Cre; Trmt10c) to specifically delete Trmt10c in the hematopoietic system. Notably, we were unable to obtain viable Trmt10c-deficient offspring, suggesting embryonic lethality. We therefore analyzed fetal liver hematopoiesis at embryonic day 14.5 (E14.5). Knockout fetal livers exhibited an accumulation of Lin−Sca1+cKit+ (LSK) and Lin−Sca1−cKit+ (LK) populations. Further analysis revealed an expansion of Pre-MegE progenitors, accompanied by a failure in erythroid lineage commitment. To elucidate the molecular mechanisms, we performed RNA-seq and Ribo-seq analysis. RNA-seq revealed significant downregulation of oxidative phosphorylation–related genes in the knockout group, alongside upregulation of genes associated with coagulation. Ribo-seq analysis indicated activation of the AKT/mTOR signaling pathway, resulting in enhanced global protein translation, particularly of membrane-associated proteins.
In conclusion, our study identifies TRMT10C as a critical regulator of hematopoietic development. Its loss disrupts erythropoiesis by altering mitochondrial function and activating the AKT/mTOR pathway, thereby impairing the metabolic and translational landscape required for proper hematopoietic differentiation.
{"title":"3041 – LOSS OF TRMT10C DISRUPTS HEMATOPOIETIC DEVELOPMENT THROUGH AKT/MTOR-DRIVEN TRANSLATIONAL CONTROL","authors":"Yimeng Gao , Xiaojie Hu , Yue Jiang , Renjie Yu , Yirui He , Hua-Bing Li","doi":"10.1016/j.exphem.2025.104982","DOIUrl":"10.1016/j.exphem.2025.104982","url":null,"abstract":"<div><div>Hematopoiesis is a tightly regulated process that requires a metabolic switch from glycolysis to mitochondrial respiration. However, the underlying mechanisms remain poorly understood. TRMT10C, a mitochondrial m1A methyltransferase, is highly expressed in hematopoietic stem and progenitor cells. Recent studies have linked missense mutations in TRMT10C to the rare autosomal recessive disorder oxidative phosphorylation deficiency 30, highlighting its clinical relevance. This prompted us to investigate the role of TRMT10C-mediated N1-methylation at position nine of mitochondrial tRNAs in hematopoiesis.</div><div>We generated a conditional knockout mouse model (Vav1-Cre; Trmt10c) to specifically delete Trmt10c in the hematopoietic system. Notably, we were unable to obtain viable Trmt10c-deficient offspring, suggesting embryonic lethality. We therefore analyzed fetal liver hematopoiesis at embryonic day 14.5 (E14.5). Knockout fetal livers exhibited an accumulation of Lin−Sca1+cKit+ (LSK) and Lin−Sca1−cKit+ (LK) populations. Further analysis revealed an expansion of Pre-MegE progenitors, accompanied by a failure in erythroid lineage commitment. To elucidate the molecular mechanisms, we performed RNA-seq and Ribo-seq analysis. RNA-seq revealed significant downregulation of oxidative phosphorylation–related genes in the knockout group, alongside upregulation of genes associated with coagulation. Ribo-seq analysis indicated activation of the AKT/mTOR signaling pathway, resulting in enhanced global protein translation, particularly of membrane-associated proteins.</div><div>In conclusion, our study identifies TRMT10C as a critical regulator of hematopoietic development. Its loss disrupts erythropoiesis by altering mitochondrial function and activating the AKT/mTOR pathway, thereby impairing the metabolic and translational landscape required for proper hematopoietic differentiation.</div></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"151 ","pages":"Article 104982"},"PeriodicalIF":2.1,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145620332","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}
Pub Date : 2025-11-01DOI: 10.1016/j.exphem.2025.104901
Atsushi Iwama
Children with Down syndrome (DS) have an increased risk of developing myeloid leukemia (ML-DS), particularly acute megakaryoblastic leukemia (AMKL), which is characterized by the presence of a truncated form of GATA1 (GATA1s). However, the contribution of concurrent somatic gene mutations to leukemogenesis remains incompletely understood. Notably, mutations in cohesin and polycomb repressive complex 2 (PRC2) genes are particularly frequent in ML-DS, with a substantial proportion of patients harboring both. Here, we demonstrated that deletion of the cohesion gene STAG2 and/or the PRC2 component EZH2 in GATA1s-expressing fetal liver cells engrafted into recipient mice induces abnormal megakaryocytopoiesis accompanied by lethal fibrosis. Moreover, the expression of chromosome 21-encoded miR-125b promotes the expansion of GATA1s-expressing megakaryocytic progenitors and blocks their differentiation in culture, but only in the absence of STAG2 and/or EZH2. This cooperative effect results in the development of AMKL in mice when both genes are deleted. Mechanistically, GATA1s, in combination with STAG2 and/or EZH2 deletion, promote biased differentiation toward the megakaryocytic lineage and enhance megakaryocytic progenitor expansion. Although GATA1s alone is known to increase the global H3K27me3 levels through an unclear mechanism, loss of EZH2 profoundly reduces H3K27me3, and notably, loss of STAG2 also leads to moderate reduction. As a result, the combination of GATA1s with either STAG2 or EZH2 loss establishes a PRC2-insufficient state. These findings suggest that epigenetic remodeling of the GATA1s-driven preleukemic state by additional somatic gene mutations, particularly in STAG2 and EZH2, is a critical step in the pathogenesis of ML-DS.
{"title":"1021 – DYSREGULATED POLYCOMB REPRESSIVE COMPLEX 2 UNDERLIES THE DEVELOPMENT OF MYELOID LEUKEMIA ASSOCIATED WITH DOWN SYNDROME","authors":"Atsushi Iwama","doi":"10.1016/j.exphem.2025.104901","DOIUrl":"10.1016/j.exphem.2025.104901","url":null,"abstract":"<div><div>Children with Down syndrome (DS) have an increased risk of developing myeloid leukemia (ML-DS), particularly acute megakaryoblastic leukemia (AMKL), which is characterized by the presence of a truncated form of GATA1 (GATA1s). However, the contribution of concurrent somatic gene mutations to leukemogenesis remains incompletely understood. Notably, mutations in cohesin and polycomb repressive complex 2 (PRC2) genes are particularly frequent in ML-DS, with a substantial proportion of patients harboring both. Here, we demonstrated that deletion of the cohesion gene <em>STAG2</em> and/or the PRC2 component <em>EZH2</em> in <em>GATA1s</em>-expressing fetal liver cells engrafted into recipient mice induces abnormal megakaryocytopoiesis accompanied by lethal fibrosis. Moreover, the expression of chromosome 21-encoded <em>miR-125b</em> promotes the expansion of <em>GATA1s</em>-expressing megakaryocytic progenitors and blocks their differentiation in culture, but only in the absence of <em>STAG2</em> and/or <em>EZH2</em>. This cooperative effect results in the development of AMKL in mice when both genes are deleted. Mechanistically, GATA1s, in combination with <em>STAG2</em> and/or <em>EZH2</em> deletion, promote biased differentiation toward the megakaryocytic lineage and enhance megakaryocytic progenitor expansion. Although GATA1s alone is known to increase the global H3K27me3 levels through an unclear mechanism, loss of EZH2 profoundly reduces H3K27me3, and notably, loss of STAG2 also leads to moderate reduction. As a result, the combination of GATA1s with either STAG2 or EZH2 loss establishes a PRC2-insufficient state. These findings suggest that epigenetic remodeling of the GATA1s-driven preleukemic state by additional somatic gene mutations, particularly in STAG2 and EZH2, is a critical step in the pathogenesis of ML-DS.</div></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"151 ","pages":"Article 104901"},"PeriodicalIF":2.1,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145620265","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}
During development, the interaction between hematopoietic stem and progenitor cells (HSPCs) and the fetal liver niche is critical for stem cell programming and maturation. However, the genetic regulatory networks involved are poorly understood. To dissect these networks, we used a viable integrin α4 (itga4) mutant zebrafish where HSPCs fail to lodge in the caudal hematopoietic tissue (CHT), the zebrafish equivalent of the fetal liver. HSPCs expressing itga4 attach to the CHT niche via vascular cell adhesion molecule 1b (vcam1b) expressed on endothelial and mesenchymal stromal cells. This contact initiates chromatin remodeling in HSPCs to close peaks enriched for activator protein 1 (AP-1) motifs and open peaks enriched for GATA motifs. Together, this downregulates inflammatory pathways that were required for HSPC emergence from the dorsal aorta at earlier stages. Disruption of itga4-vcam1b and bypass of the CHT niche keeps HSPCs in a proliferative state throughout development and in adulthood, resulting in adult marrow with a more inflammatory and myeloid-biased profile. We show that HSPC-niche contact during development is necessary for programming embryonic HSPCs as they transition to quiescence in adulthood.
{"title":"1014 – NICHE CONTACT DURING DEVELOPMENT PROGRAMS HEMATOPOIETIC STEM CELLS","authors":"Owen Tamplin , Nicole Woodhead , Octavia Santis Larrain , Sobhika Agarwala , Alice Alhajkadour , Kylie Sweeny , Wantong Li , Bradley Blaser , Clyde Campbell , Rodolfo Calderon , Raquel Espin-Palazon , Khaliun Enkhbayar , Elliott Hadedorn","doi":"10.1016/j.exphem.2025.104894","DOIUrl":"10.1016/j.exphem.2025.104894","url":null,"abstract":"<div><div>During development, the interaction between hematopoietic stem and progenitor cells (HSPCs) and the fetal liver niche is critical for stem cell programming and maturation. However, the genetic regulatory networks involved are poorly understood. To dissect these networks, we used a viable integrin α4 (itga4) mutant zebrafish where HSPCs fail to lodge in the caudal hematopoietic tissue (CHT), the zebrafish equivalent of the fetal liver. HSPCs expressing itga4 attach to the CHT niche via vascular cell adhesion molecule 1b (vcam1b) expressed on endothelial and mesenchymal stromal cells. This contact initiates chromatin remodeling in HSPCs to close peaks enriched for activator protein 1 (AP-1) motifs and open peaks enriched for GATA motifs. Together, this downregulates inflammatory pathways that were required for HSPC emergence from the dorsal aorta at earlier stages. Disruption of itga4-vcam1b and bypass of the CHT niche keeps HSPCs in a proliferative state throughout development and in adulthood, resulting in adult marrow with a more inflammatory and myeloid-biased profile. We show that HSPC-niche contact during development is necessary for programming embryonic HSPCs as they transition to quiescence in adulthood.</div></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"151 ","pages":"Article 104894"},"PeriodicalIF":2.1,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145620374","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}
Pub Date : 2025-11-01DOI: 10.1016/j.exphem.2025.104972
Quynh Nguyen , Vladimir Manchev , Greg Kent , Donghe Yang , Jamie Kwan , Brenda Cohen , Marion Kennedy , Ian Fernandes , Paraish Misra , Mark Gagliardi , Gordon Keller
The generation of human pluripotent stem cell (hPSC)-derived hematopoietic progenitors for specific therapeutic applications is dependent on the accurate specification of the appropriate hematopoietic program in the dish. Using developmental biology-guided approaches, differentiation protocols have been established, generating the equivalent of the yolk sac (YS) primitive and EMP/LMPP programs as well as an ‘intraembryonic’ definitive program. Recent significant advances include the successful generation of hematopoietic stem cells (HSCs) from the definitive program and the discovery of a YS multipotent progenitor (YS MPP) population specified by the EMP/LMPP program. However, the low frequencies of these cells in the differentiation cultures limit their downstream therapeutic applications. As hematopoietic fates are specified early at the mesoderm induction stage, the inefficient generation of a particular hematopoietic cell type likely stems from the failure to specify the appropriate mesoderm subset. To address this, we have identified a novel set of markers that effectively resolve the heterogeneity within the hematopoietic mesoderm populations, in turn establishing a new model of the embryonic hematopoietic development. Specifically, cell sorting studies revealed that the fates of primitive and YS MPP programs, and, likely, of definitive HSC-independent MPP and HSC programs, are specified from distinct mesoderm populations. These subsets of mesoderm differ in their signaling requirements, kinetics of development, and developmental potential. Collectively, these findings established a novel, comprehensive developmental map of the human hematopoietic system, enabling the precise specification of distinct hematopoietic programs and, in turn, the generation of the otherwise inaccessible hematopoietic progenitors essential for the development of future cell therapies.
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Pub Date : 2025-11-01DOI: 10.1016/j.exphem.2025.104893
Claudia Waskow
This presentation will explore the role of embryonic versus adult macrophages in establishing the hematopoietic stem cell niche. It will also discuss the impact of the developmental origin of macrophages on both immune cell homeostasis and overall immune function.
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