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PubMed2026

Tropomyosin 1 Promotes Platelet Adhesion and Clot Contraction Separate from Its Roles in Developmental Hematopoiesis.

Genome-wide association studies (GWAS) link the Tropomyosin 1 (Tpm1) locus to quantitative blood trait variation, but related mechanisms are unclear. Tpm1 encodes an actin-binding protein that regulates actin filament diversity, cell adhesion, signaling, and actomyosin contractility. Murine Tpm1 deficiency enhances hemogenic endothelial cell (HEC) specification, but it was unclear if these effects extended to postnatal hematopoiesis. We used Cdh5Cre and VavCre models to conditionally knock out Tpm1 (Tpm1KO) in endothelial anor hematopoietic cells. Both models ablate Tpm1 in postnatal blood. Endothelial Tpm1KO increases HEC specification without altering hematopoietic progenitor cell production or adult blood counts, suggesting separate roles for Tpm1 in the embryonic and adult blood systems. Tpm1KO increases adult platelet lifespan and diminishes adhesion to fibronectin and fibrinogen. Chemical Tpm1 inhibition also reduces focal adhesion in murine and human platelets. Altered platelet morphology and reduced platelet spreading suggest perturbed actomyosin contractility underlies these findings. Platelet fibrin binding promotes blood clot contraction, which reduces occlusive thrombosis. Tpm1KO limits clot contraction and worsens vascular occlusion in ferric chloride-induced stroke models. In addition to offering a mechanistic explanation for why genetic variation at the TPM1 alters platelet traits in GWAS, our findings reveal novel roles for Tpm1 in clot contraction and thrombosis.

Animals↗

PubMed2026

Cell-of-origin Discovery in Infant Leukemia through Integration of 3D Models and Patient Transcriptomic Data.

Pediatric hematological malignancies remain challenging to investigate and model due to the age group-specificity of certain genetic abnormalities. In utero origin has been demonstrated for a subset of pediatric leukemias, placing their respective cell of origin (CoO) during embryonic development. We recently reported a 3D hemogenic gastruloid (haemGx) model of embryonic blood formation derived from mouse embryonic stem cells, resolving the spatio-temporal complexity of developmental hematopoiesis. Importantly, it allows genetic engineering to introduce disease-relevant mutations. Using haemGx, we modeled the most common acute myeloid leukemia exclusive to infants (infAML), subtype t(7;12)(q36;p13), which arises in utero and is characterized by MNX1 overexpression. Here, we detail a method to define susceptibility to specific mutations that integrate phenotypic and transcriptional changes in the haemGx system and compares them with patient data. By proxy of our MNX1-overexpression haemGx, we show a pipeline from cell engineering to downstream analyses of leukemogenic potential. In particular, we focus on the clinical relevance of the model by integrating single-cell and/or bulk RNA sequencing from the haemGx platform with patient data to extract cellular composition and temporal placement of the putative CoO. This method is adaptable to the introduction of other oncogenic mutations, chromosomal rearrangements, or epigenetic modifications, as well as to chemical perturbations, including drug vulnerability and growth factor dependence. This flexibility allows for broad application across diverse disease contexts, enabling mechanistic dissection of how specific alterations disrupt early developmental trajectories with clinical relevance.

Humans↗

PubMed2025

Differentiation latency and dormancy signatures define fetal liver hematopoietic stem cells at single-cell resolution.

Decoding the mechanisms governing the self-renewal of hematopoietic stem cells (HSCs) during their expansion in the fetal liver (FL) could unlock novel therapeutic strategies to expand transplantable HSCs, a long-standing challenge. To explore intrinsic and extrinsic regulation of FL-HSC self-renewal at single-cell resolution, we engineered a culture platform replicating the FL endothelial niche that supports the amplification of serially engraftable HSCs. Leveraging this platform together with single-cell index flow cytometry, live imaging, transplantation assays, and single-cell RNA sequencing, we demonstrate that differentiation latency, cell-division symmetry, and transcriptional signatures of biosynthetic dormancy are distinguishing properties of rare FL-HSCs capable of serial multilineage hematopoietic reconstitution. Our findings support a paradigm in which intrinsic programs and niche-derived signals together facilitate the symmetric self-renewal of FL-HSCs while delaying their active participation in hematopoiesis. Our study also provides a resource for future investigations into intrinsic and extrinsic signaling pathways governing FL-HSC self-renewal.

Hematopoietic Stem Cells↗

PubMed2026

Regulation of TET function by PROSER1 in development and hematologic malignancies.

Ten eleven translocation (TET) proteins are central regulators of DNA methylation homeostasis and play essential roles in development and disease, including hematopoietic malignancies. Among the three TET family members, mutations in TET2 are frequently observed in hematologic disorders. TET enzymes catalyze the iterative oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and further oxidized derivatives, enabling DNA demethylation. Beyond catalysis, TET proteins also perform important non-enzymatic functions mediated through interactions with diverse protein partners, highlighting the importance of defining their regulatory interactome. Previous studies identified several TET-associated factors, including O-Linked N-acetylglucosamine transferase (OGT), members of the Drosophila behavior/human splicing (DBHS) protein family, and proline and serine-rich protein 1 (PROSER1). However, these interactions were largely considered independently. Recent findings now demonstrate that TET proteins, OGT, PROSER1, and DBHS proteins assemble into a higher-order regulatory unit termed the TOPD (TET-OGT-PROSER1-DBHS) complex. In this review, we discuss how TOPD provides a conceptual framework for understanding multicomponent regulation of TET function, spatial control of DNA demethylation, and maintenance of epigenetic homeostasis, with implications for developmental syndromes and hematopoiesis.

Humans↗

PubMed2026

The minor spliceosome component U4atac regulates JAK/STAT signaling to modulate hematopoiesis and immune responses in Drosophila melanogaster.

The small nuclear RNA U4atac is a core component of the minor spliceosome. In humans, homozygous or compound heterozygous point mutations in U4atac cause rare developmental disorders, such as Roifman syndrome, characterized by growth restriction, brain anomalies, and immune deficiency. To better define the pathophysiological role of U4atac mutations, we here establish a model of minor spliceosome dysfunction by generating a Drosophila melanogaster CRISPR/Cas9-induced U4atac mutant in the highly conserved stem II region. U4atac homozygous mutants exhibit growth and neurodevelopmental defects, immunodeficiency, and gastrointestinal symptoms. Using bulk RNA-sequencing and functional assays, we reveal that mutations in U4atac affect the splicing of a large set of transcripts involved in innate immunity, hematopoiesis, and intestinal cell functions, including the Drosophila Janus kinase (JAK) homolog hopscotch (hop). Importantly, U4atac deficiency reduces Hop expression and causes Hop-related hematopoietic defects at the embryonic and larval stages. Notably, we also observe reduced expression of Jak1 and attenuated activation of downstream signaling in patients with Roifman syndrome. Thus, our work identifies alterations of Jak signaling as part of the pathogenesis of RNU4atac-opathy.

Animals↗

PubMed2026

The machine-learning classifier ALLCatchR2 identifies 20 T-ALL subtypes across cohorts and age groups.

T-cell acute lymphoblastic leukemia (T-ALL) comprises molecularly diverse subtypes, but robust cross-cohort validations and operational gene-expression definitions are lacking. To establish a gene-expression-anchored framework for T-ALL subtyping, we aggregated 2314 transcriptomes (15 cohorts, age: 0.8-90.8 years). An extended unsupervised approach defined 17 main clusters and 3 subclusters in samples with high blast fractions. Supervised analyses added an overarching immature T-ALL (early T cell precursor [ETP]-like) definition and resolved the LMO2 γδ-like subtype. All clusters contained samples from at least two cohorts. Characteristic genomic driver enrichments were consistent across cohorts, while gene-expression clusters did not correspond exclusively to single driver events but also reflected developmental origins. A machine-learning classifier based on ALLCatchR, our B-cell acute lymphoblastic leukemia (B-ALL) classifier, identified these 20 transcriptomic subtypes and the immature T-ALL (ETP-like) signature with 0.995-1.0 accuracy in a validation set (n = 203). Testing the classifier on a second hold-out data set (n = 265 samples) showed that 92.7% of predictions matched with corresponding driver alterations. Across all samples, 83.2% of cases received high-confidence predictions, 7.3% candidate predictions, and 9.5% remained unclassified, largely because of low blast fractions. We identified a novel gene-expression cluster markedly enriched (P < 0.001) for clonal hematopoiesis mutations (IDH2 R140Q, DNMT3A) and a stem-/progenitor cell-like gene expression. This novel clonal hematopoiesis-related T-ALL subtype was observed in six cohorts and accounted for 8.9% of adults and 39.5% of patients aged >50 years. We extended ALLCatchR into ALLCatchR2, a free R package that now enables B-/T-lineage separation, gene-expression subtyping, blast estimation, and developmental annotation to harmonize T-ALL classification across studies and clinical contexts.

Journal Article↗

PubMed2026

RNA Binding Protein PCBP1 Functions in the Endothelial-to-Hematopoietic Transition During Hematopoietic Stem Cell Formation.

Two paralogous RNA-binding proteins, PCBP1 and PCBP2, are individually essential for mouse development. Pcbp2-null embryos lose viability at midgestation, whereas Pcbp1-null embryos have an earlier, peri-implantation lethality. Inactivation of each gene alone in the differentiating erythroid lineage failed to impact embryonic viability, whereas combined Pcbp1/Pcbp2 inactivation resulted in repression of erythroid/hematopoietic gene expression midgestation, decreased blood cell formation, and fetal demise. Here, we assess the impacts of individual and combined conditional inactivation of Pcbp1 and Pcbp2 in endothelial cells on embryonic hematopoietic stem and progenitor cell (HSPC) formation. Inactivation of Pcbp1 in endothelial cells is embryonic lethal and reduces the number of HSPCs, whereas loss of Pcbp2 has no impact. Combined deletion of Pcbp1 and Pcbp2 in endothelial cells results in a more severe phenotype than loss of Pcbp1 alone. These results demonstrate that although Pcbp1 is a major regulator of HSPC formation, the two genes have nonredundant roles in endothelial cells.

Animals↗

PubMed2026

Environmental benzene exposure induces a conserved neutrophil degranulation program across species.

Immune systems have evolved under constant pressure from pathogens and environmental challenges, leading to the emergence of conserved defense mechanisms across diverse organisms. Evidence indicates that environmental exposures perturb immune regulatory networks, particularly during development, when transcriptional programs governing hematopoiesis, immune cell differentiation, and inflammatory signaling are highly dynamic and sensitive to external stressors. Volatile organic compounds represent an important but incompletely understood source of immunological perturbation. Among these, benzene is a ubiquitous environmental contaminant associated with hematotoxicity and immune dysregulation; however, transcriptional responses to environmentally relevant low-level exposures during development remain poorly characterized. To determine whether benzene exposure engages conserved cross-species immune regulatory pathways, we performed a comparative transcriptomic analysis integrating developmental tissues from 3 vertebrate systems: human placenta, murine placenta, and zebrafish larvae. Bulk RNA sequencing datasets were analyzed to identify transcriptional responses associated with benzene exposure in experimental models (≤5 ppm) and with benzene adduct levels in maternal plasma for human samples. Because placental gene expression exhibits strong sexual dimorphism, murine datasets were stratified by fetal sex. Pathway- and network-level analyses were used to identify conserved biological responses. We observed a striking convergence on activation of innate immune pathways associated with neutrophil degranulation, IL-8 signaling, and Rho GTPase-mediated inflammatory responses. Further, network analyses identified CXCL8 and ERK1/2 as shared regulatory hubs linking transcriptional responses across datasets. Together, these findings uncover an evolutionarily conserved innate immune signature associated with benzene exposure during vertebrate development, suggesting that environmental chemical perturbations may disrupt fundamental immune regulatory programs across species.

Animals↗

PubMed2025

Impaired hematopoiesis and embryonic lethality at midgestation of mice lacking both lipid transfer proteins VPS13A and VPS13C.

VPS13 is the founding member of a family of proteins that mediate lipid transfer at intracellular membrane contact sites by a bridge-like mechanism. Mammalian genomes comprise 4 VPS13 genes encoding proteins with distinct localizations and function. The gene duplication resulting in VPS13A and VPS13C is the most recent in evolution and, accordingly, these two proteins are the most similar to each other. However, they have distinct subcellular localizations and their loss of function mutations in humans are compatible with life but result in two different age-dependent neurodegenerative diseases, chorea-acanthocytosis and Parkinson's disease, respectively. Thus, it remains unclear whether these two proteins have overlapping functions. Here, we show that while Vps13a KO and Vps13c KO mice are viable, embryonic development of Vps13a/Vps13c double knockout (DKO) mice is arrested at midgestation. Prior to death, DKO embryos were smaller than controls, were anemic and had a smaller liver, most likely reflecting defective embryonic erythropoiesis which at this developmental stage occurs primarily in this organ. Further analyses of erythroid precursor cells showed that their differentiation was impaired and that this defect was accompanied by activation of innate immunity as revealed by upregulation of interferon stimulated genes (ISGs). Additionally, the RIG-I and MDA5 components of dsRNA triggered innate immunity were found upregulated in the DKO fetal liver. Activation of innate immunity may result from loss of integrity of the membranes of intracellular organelles, such as mitochondria and autophagic lysosomes, or to impaired autophagy, due to the absence of these lipid transport proteins. The surprising and striking synthetic effect resulting for the combined loss of VPS13A and VPS13C suggests that despite of the different localization of these two proteins, the lipid fluxes that they mediate are partially redundant.

Animals↗

PubMed2026

Genomic basis of developmental defects of enamel and sex-specific effects.

We conducted a multi-ancestry genome-wide association study (GWAS) of developmental defects of enamel (DDE) in the primary dentition among 6,061 U.S. preschool-aged children (3-5 years). We investigated four DDE phenotypes (demarcated opacities, diffuse opacities, hypoplastic defects, and a combined DDE trait) leveraging main-effect models, joint gene-sex interaction testing (2df), and sex-stratified analyses. SNP-based heritability for the combined DDE trait was estimated at 20%, with concordance analyses robustly supporting a genetic etiology. We identified 39 unique genome-wide significant loci (P<5×10 ), with five surpassing a study-wide Bonferroni-corrected statistical significance criterion (P<1.25×10 9), including Y RNA and ALDH1A1. The main-effect GWAS identified 20 loci, including HBS1L and MYB, genes regulating hematopoiesis with plausible roles in amelogenesis. Joint test and sex-stratified analyses revealed 19 additional loci, including ALDH1A1, TENM2, and DLGAP2, demonstrating sex-specific heterogeneity. Nineteen loci exhibited sex-specific differences after Bonferroni correction (P<2x10-3), including genes involved in retinoic acid signaling (ALDH1A1), odontogenesis (TENM2), and neurodevelopment (DLGAP2, CDH10). Pathway enrichment highlighted ectodermal and synapse organization networks, suggesting shared etiological mechanisms between DDE and systemic conditions like neurofibromatosis and autism spectrum disorder. Notably, no locus generalized in an external GWAS of permanent dentition DDE, underscoring fundamental biological differences in the genetic architectures governing primary versus permanent enamel formation. Crucially, a comprehensive cross-trait pleiotropy lookup against early childhood caries (ECC) revealed no shared genetic architecture, supporting the notion that the established clinical and epidemiological association between DDE and ECC is likely driven by structural defects increasing caries lesion susceptibility rather than genetic pleiotropy. By integrating gene-sex interaction testing, this study offers novel insights into the complex, sexually dimorphic genetic etiology of DDE and augments the biological evidence base that can support the development of precision pediatric dentistry.

developmental defects of enamel↗

PubMed2026

Endothelial PERK restricts lymphoid regeneration by reducing DLL4-NOTCH3 signaling at the Pre-B niche.

Delayed immune recovery after hematopoietic stem cell (HSC) transplantation is associated with a poor clinical outcome. We study the role of unfolded protein response (ER stress) in hematopoietic regeneration within the bone marrow (BM) microenvironment. We reveal that BM endothelium PERK activation is a prominent feature of patients with leukemia and is a hallmark response in mice following ionizing irradiation. Ablating endothelial Perk boosts NOTCH ligand DLL4 expression and promotes DLL4-dependent early HSC and B progenitor regeneration. Single-cell analysis reveals that endothelial DLL4 activates NOTCH3 expressed by mesenchymal stroma cells, and that the PERK-DLL4 axis coordinates the regulation of lymphoid commitment. NOTCH3 is critical for the upregulation of IL7 following irradiation and the expansion of lymphoid progenitors. These findings not only unveil an ER stress-controlled vascular-stroma signaling mechanism in regenerative hematopoiesis but also highlight PERK blockade as a promising strategy to improve immune recovery after myeloablative transplantation.

CP: cell biology↗

PubMed1978

[Differentiation of hematopoietic cells in explants of embryonal organs of Rana temporaria L].

The potencies of isolated embryonic hemopoietic organs (pronephros and liver) of Rana temporaria L. to the formation of the foci of hemopoiesis were studied. The pronephros and liver rudiments were explanted at the early developmental stages (late neurula and early tail bud) and cultivated in vivo in the diffusion chambers. The blast hemopoietic elements and differentiated blood cells are found in the explants within 7 to 10 days of cultivation. A suggestion is put forward that the differentiation of hemopoietic cells in the embryonic hemopoietic organs proceeds from the local cells-precursors.

Animals↗

PubMed2025

Histone modifications in the regulation of erythropoiesis.

INTRODUCTION: The pathogenesis of anemia and other erythroid dysphasia are mains poorly understood, primarily due to limited knowledge about the differentiation processes and regulatory mechanisms governing erythropoiesis. Erythropoiesis is a highly complex and precise biological process, that can be categorized into three distinct stages: early erythropoiesis, terminal erythroid differentiation, and reticulocyte maturation, and this complex process is tightly controlled by multiple regulatory factors. Emerging evidence highlights the crucial role of epigenetic modifications, particularly histone modifications, in regulating erythropoiesis. Methylation and acetylation are two common modification forms that affect genome accessibility by altering the state of chromatin, thereby regulating gene expression during erythropoiesis. DISCUSSION: This review systematically examines the roles of histone methylation and acetylation, along with their respective regulatory enzymes, in regulating the development and differentiation of hematopoietic stem/progenitor cells (HSPCs) and erythroid progenitors. Furthermore, we discuss the involvement of these histone modifications in erythroid-specific developmental processes, including hemoglobin switching, chromatin condensation, and enucleation.Conclusions This review summarizes the current understanding of the role of histone modifications in erythropoiesis based on existing research, as a foundation for further research the mechanisms of epigenetic regulatory in erythropoiesis.

Erythropoiesis↗

PubMed1978

Developmental relationships between vitelline and intra-embryonic haemopoiesis studied in avian 'yolk sac chimaeras'.

Using the quail-chick marker technique, cells have been traced in the haemopoietic organs of 149 developing chimaeras composed of a quail embryo with a chick yolk sac. The existence of intraembryonic stem cell relaying yolk sac stem cells, previously demonstrated with this system, is confirmed. Thymus, bursa of Fabricius and bone marrow are preferentially populated by intraembryonic stem cells. The spleen shows a transitory phase of colonization by chick yolk sac stem cells at 11--12 days of incubation. From 7 days onwards the yolk sac receives quail stem cell emigrating from the embryo.

Animals↗

PubMed1977

In vitro activation of the in vivo colony-forming units of the mouse yolk sac.

Experiments were performed to investigate the presence of colony-forming units (CFU) in the mouse embryonic yolk sac during the developmental period in which the yolk sac is the sole hemopoietic organ. Injection of yolk sac cell suspensions from normal embryos into syngeneic, lethally irradiated adult recipients evoked a very low number of spleen colonies. However, prior cultivation of yolk sacs in vitro caused a dramatic increase in the spleen colony-forming capacity--as high as 84-fold--following 48 hours in culture. The yolk sac origin of the spleen colonies was confirmed by: (a) Chromosomal marker analysis; (b) dose-response analysis; (c) demonstrating that the above colonies were not of endogenous origin induced by the mere injection of grafted cells. We conclude that the yolk sac contains many precursors of colony-forming cells which though undetectable by immediate grafting apparently become activated in culture by an as yet unknown induction process.

Animals↗

PubMed1977

Differentiation in human myeloblastic leukemia studied in cell culture.

Normal adult hemopoiesis orginates in pluripotent stem cells; among the early differentiated descendents of such cells are progenitors committed to the erythropoietic, granulopoietic, or megakaryocytic pathways of myeloid differentiation. These may be detected in cell culture by developmental techniques, in which progenitors form colonies in viscid or semisolid media in response to appropriate stimulation. Certain diseases of hemopoiesis also originate in pluripotent stem cells; these include chronic myeloblastic leukemia, acute myeloblastic leukemia, polycythemia vera, and idiopathic myelofibrosis-the clonal hemopathies. The hypothesis is advanced that the distribution of cell classes among patients with clonal hemopathies is determined both by the differentiation potential of each pluripotent stem cell maintaining an abnormal clone and by random events occurring during clonal expansion. The latter process may account for the large variations observed between patients when committed progenitors are assayed in cultures of marrow from patients with acute myeloblastic leukemia (AML). This variation may also be used to estimate lineage relationships in the clonal hemopathies. When applied to myelopoiesis in AML, obvious differences from the normal are not detected. The analysis is consistent with the view that the blast cell population in AML is distinct from the leukemic myelopoiesis occurring within an abnormal clone. A new assay procedure is described for progenitor cells related to blast cell proliferation. Finally, these concepts are used to develop a model for the pathogenesis and cellular characteristics of AML.

Cells, Cultured↗

PubMed1978

Normal blood cells of anemic genotype in teratocarcinoma-derived mosaic mice.

In allophenic (mosaic) mice produced from blastocysts injected with teratocarcinoma stem cells of the OTT 6050 transplant line, an unexpected coat phenotype led to the discovery that the tumor-lineage cells carried the steel gene (Sl(J)/+). Because steel also causes a macrocytic anemia, mosaics comprising both genetically anemic and normal (+/+) cells fortuitously provided a unique opportunity to examine in vivo the etiology of this anemia in light of previous results indicating that the lesion is extrinsic to the erythroid cells. The experiment differs from previous ones, which involved postnatal grafting, in that here hematopoietic stem cells of anemic and normal genotypes coexist throughout all developmental stages, confronted by tissues of the hematopoietic microenvironment that consist partly or solely of genetically normal cells. Therefore, the possibility exists that the anemia might be completely prevented rather than secondarily ameliorated. Moreover, variation in proportion of normal-strain cells in the hematopoietic supporting tissues could serve to "titrate" minimal requirements to promote normal erythropoiesis. Mice with mixed populations of steel- and normal-genotype cells in blood and other tissues were identified by means of independent markers specific for tumor vs. blastocyst strains of origin. The clinical blood picture of these mosaics proved to be indistinguishable from that of normal controls, even when only a small minority of cells in all tissues of one of the animals were genetically normal. Phenotypic blood normalcy was shown, by occurrence of the typical steel anemia among F(1) germ-line progeny of mosaics, not to be due to any change in the capacity of the mutant gene to elicit the anemia. The results from the mosaics thus demonstrate that the primary expression of the steel lesion is indeed in the hematopoietic microenvironment. However, they also reveal that a surprisingly small complement of normal cells there appears to be adequate to prevent this anemia permanently. The hypothesis is advanced that relatively short-range diffusible substances, produced by cells in the microenvironment and required for normal erythropoiesis, may account for the inductive effectiveness of small cell numbers.

Anemia, Macrocytic↗