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ONTOGENY SHAPES THE ABILITY OF ETV6-RUNX1 TO ENHANCE HEMATOPOIETIC STEM CELL SELF-RENEWAL AND DISRUPT EARLY LYMPHOPOIESIS

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE239344 | GEO | 2024/01/08

REPOSITORIES: GEO

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Ontogeny shapes the ability of ETV6::RUNX1 to enhance hematopoietic stem cell self-renewal and disrupt early lymphopoiesis.

Project description: Not available

| S-EPMC10844086 | biostudies-literature

ONTOGENY SHAPES THE ABILITY OF ETV6-RUNX1 TO ENHANCE HEMATOPOIETIC STEM CELL SELF-RENEWAL AND DISRUPT EARLY LYMPHOPOIESIS [in vitro]

Project description:The ETV6-RUNX1 (E/R) translocation, found in approximately 30% of pediatric B-cell acute lymphoblastic leukemia (ALL) cases, originates prenatally. Although hematopoietic stem cells (HSCs) have been proposed as the cell of origin for E/R-ALL, definitive evidence for this has been lacking. Here, we develop an E/R-inducible transgenic mouse model and observe that E/R rapidly expands the pool of phenotypic HSCs and block early B cell development. By leveraging the reversibility of the model, we demonstrate functional rather than merely phenotypic HSC expansion. At a molecular level, E/R activates immune checkpoint pathways, which is more pronounced in fetal cells. Comparison of fetal and adult HSCs reveals that although E/R disrupts HSC differentiation in both, fetal cells have a competitive advantage, especially in a setting of viral mimicry. These findings provide new insights into the nature of preleukemic clones associated with E/R and suggest potential benefits of immune checkpoint inhibition for their eradication.

2024-01-08 | GSE239342 | GEO

ONTOGENY SHAPES THE ABILITY OF ETV6-RUNX1 TO ENHANCE HEMATOPOIETIC STEM CELL SELF-RENEWAL AND DISRUPT EARLY LYMPHOPOIESIS [in vivo]

2024-01-08 | GSE239340 | GEO

ONTOGENY SHAPES THE ABILITY OF ETV6-RUNX1 TO ENHANCE HEMATOPOIETIC STEM CELL SELF-RENEWAL AND DISRUPT EARLY LYMPHOPOIESIS

Project description:ONTOGENY SHAPES THE ABILITY OF ETV6-RUNX1 TO ENHANCE HEMATOPOIETIC STEM CELL SELF-RENEWAL AND DISRUPT EARLY LYMPHOPOIESIS

| PRJNA998835 | ENA

ONTOGENY SHAPES THE ABILITY OF ETV6-RUNX1 TO ENHANCE HEMATOPOIETIC STEM CELL SELF-RENEWAL AND DISRUPT EARLY LYMPHOPOIESIS [in vitro]

Project description:ONTOGENY SHAPES THE ABILITY OF ETV6-RUNX1 TO ENHANCE HEMATOPOIETIC STEM CELL SELF-RENEWAL AND DISRUPT EARLY LYMPHOPOIESIS [in vitro]

| PRJNA998850 | ENA

ONTOGENY SHAPES THE ABILITY OF ETV6-RUNX1 TO ENHANCE HEMATOPOIETIC STEM CELL SELF-RENEWAL AND DISRUPT EARLY LYMPHOPOIESIS [in vivo]

Project description:ONTOGENY SHAPES THE ABILITY OF ETV6-RUNX1 TO ENHANCE HEMATOPOIETIC STEM CELL SELF-RENEWAL AND DISRUPT EARLY LYMPHOPOIESIS [in vivo]

| PRJNA998849 | ENA

RUNX1 mutations enhance self-renewal and block granulocytic differentiation in human in vitro models and primary AMLs.

Project description:To unravel molecular mechanisms by which Runt-related transcription factor 1 (RUNX1) mutations contribute to leukemic transformation, we introduced the RUNX1-S291fs300X mutation in human CD34+ stem/progenitor cells and in human induced pluripotent stem cells (iPSCs). In both models, RUNX1mut overexpression strongly impaired myeloid commitment. Instead, self-renewal was enhanced, as shown, by increased long-term culture-initiating cell frequencies and enhanced colony-forming cell replating capacity. Long-term suspension cultures with RUNX1mut-transduced cord blood (CB) CD34+ cells continued for more than 100 days, during which the cells displayed an immature granulocyte-macrophage progenitor-like CD34+/CD123+/CD45RA+ phenotype. The CD34+/CD38- hematopoietic stem cell (HSC) population most likely acted as cell of origin, as HSCs provided the best long-term proliferative potential on overexpression of RUNX1mut. CEBPA expression was reduced in RUNX1mut cells, and reexpression of CEBPA partly restored differentiation. RNA-seq analysis on CB/iPSC systems and on primary patient samples confirmed that RUNX1 mutations induce a myeloid differentiation block, and that a common set of RUNX1mut-upregulated target genes was strongly enriched for gene ontology terms associated with nucleosome assembly and chromatin structure. Interestingly, in comparison with AML1-ETO binding in acute myeloid leukemias (AMLs), we found significantly distinct genomic distribution and differential expression for RUNX1mut of genes such as TCF4, MEIS1, and HMGA2 that may potentially contribute to the underlying difference in clinical outcomes between RUNX1mut and AML1-ETO patients. In conclusion, RUNX1mut appears to induce a specific transcriptional program that contributes to leukemic transformation.

| S-EPMC6373749 | biostudies-literature

Determination of ETV6-RUNX1 genomic breakpoint by next-generation sequencing.

Project description:The t(12;21)(p13;q22) ETV6-RUNX1 gene fusion is one of the most common chromosomal translocation in childhood acute lymphoblastic leukemia (ALL). It is associated with favorable prognosis. The identification of the genomic sequence of the breakpoint flanking regions of the ETV6-RUNX1 translocation should be the best strategy to monitor minimal residual disease (MRD) in patients with ETV6-RUNX1-positive ALL. In this study, the ETV6-RUNX1 translocation was sequenced by next-generation sequencing (NGS) in 26 patients with ETV6-RUNX1-positive ALL and re-sequenced by using the Sanger method. Interestingly, the three-way translocation, including ETV6-RUNX1, was detected in five patients. Four of them relapsed during or after therapy, while 21 patients without the three-way translocation were still in remission (P < 0.0001). The three-way translocation pattern was identical between the diagnosis and relapse samples in three patients, excluding one patient (SCMC-001245). The relapse samples retained the translocation of ETV6-RUNX1 relative to the three-way translocation t(8;12;21) at diagnosis, suggesting that the three-way translocation might be an important risk factor for relapse in patients with ETV6-RUNX1-positive ALL and should be further studied.

| S-EPMC4735785 | biostudies-other

Molecular and pharmacological heterogeneity of ETV6::RUNX1 acute lymphoblastic leukemia.

Project description:ETV6::RUNX1 is the most common fusion gene in childhood acute lymphoblastic leukemia (ALL) associated with favorable prognosis, but the optimal therapy for this subtype remains unclear. Profiling the genomic and pharmacological landscape of 194 pediatric ETV6::RUNX1 ALL cases, we uncover two transcriptomic clusters, C1 (61%) and C2 (39%). Compared to C1, the C2 subtype features higher white blood cell counts and younger age at diagnosis, as well as better early treatment responses. Pharmacologically, C2 is more sensitive to thiopurines and prednisolone, partially explained by the enrichment of PAX5 deletions. Re-introducing PAX5 in ETV6::RUNX1 ALL of the C2 subtype converts its gene expression and drug resistance profile to C1, with partial blockade of G1 to S transition mediated by CDK6 expression. Our results point to molecular heterogeneity within ETV6::RUNX1 ALL linked to divergent drug responses, providing insights into the pathogenesis and therapeutic vulnerability of this common pediatric ALL subtype.

| S-EPMC11779914 | biostudies-literature

Glucocorticoid agonists enhance retinal stem cell self-renewal and proliferation.

Project description:BackgroundAdult mammalian retinal stem cells (RSCs) readily proliferate, self-renew, and generate progeny that differentiate into all retinal cell types in vitro. RSC-derived progeny can be induced to differentiate into photoreceptors, making them a potential source for retinal cell transplant therapies. Despite their proliferative propensity in vitro, RSCs in the adult mammalian eye do not proliferate and do not have a regenerative response to injury. Thus, identifying and modulating the mechanisms that regulate RSC proliferation may enhance the capacity to produce RSC-derived progeny in vitro and enable RSC activation in vivo.MethodsHere, we used medium-throughput screening to identify small molecules that can expand the number of RSCs and their progeny in culture. In vitro differentiation assays were used to assess the effects of synthetic glucocorticoid agonist dexamethasone on RSC-derived progenitor cell fate. Intravitreal injections of dexamethasone into adult mouse eyes were used to investigate the effects on endogenous RSCs.ResultsWe discovered that high-affinity synthetic glucocorticoid agonists increase RSC self-renewal and increase retinal progenitor proliferation up to 6-fold without influencing their differentiation in vitro. Intravitreal injection of synthetic glucocorticoid agonist dexamethasone induced in vivo proliferation in the ciliary epithelium-the niche in which adult RSCs reside.ConclusionsTogether, our results identify glucocorticoids as novel regulators of retinal stem and progenitor cell proliferation in culture and provide evidence that GCs may activate endogenous RSCs.

| S-EPMC7831262 | biostudies-literature

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