Ontology highlight
ABSTRACT:
PROVIDER: PRJNA912234 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR22742706_1.fastq.gz | Fastqsanger.gz | |||
| SRR22742706_2.fastq.gz | Fastqsanger.gz | |||
| SRR22742707_1.fastq.gz | Fastqsanger.gz | |||
| SRR22742707_2.fastq.gz | Fastqsanger.gz | |||
| SRR22742708_1.fastq.gz | Fastqsanger.gz |
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Project description:Immune stress suppresses innate immune signaling in preleukemic precursor B cells to cause leukemia
| PRJNA915055 | ENA
Project description:We used microarrays to investigate gene expression changes in leukemic bone marrow from Pax5+/-;Myd88+/- mice compared with bone marrow precursor B cells from WT mice and to study the effect of Myd88 downregulation in healthy Pax5+/- proB cells. The initial steps of B-cell acute lymphoblastic leukemia (B-ALL) development usually pass unnoticed in children; germline or somatic alterations affecting transcription factor genes cause the appearance of preleukemic cells still compatible with normal hematopoiesis, and preclinical studies have shown that immune stressors can trigger the malignant transformation of these otherwise silent preleukemic precursors to full-blown B-ALL. Understanding how exposure to immune stressors drives this conversion is a longstanding and unsolved challenge. Here we unveiled a specific “gene/environmental factor” interaction triggering B-ALL development. Our data show that B-ALL development falls into the category of cancers associated with dysregulation of innate immunity, which plays a driving role in the clonal evolution of pre-malignant B-cell precursors toward B-ALL following exposure to an immune stress. Transcriptional profiling of B-ALL allowed the identification of an inflammation-dependent role for Myd88 as a key player in this process. A preleukemic B-cell-autonomous role was evidenced by a significant increase in B-ALL incidence upon Myd88 dowregulation in the leukemia-prone Pax5+/- model. Likewise, early innate immune response induction by Toll-like receptor (TLR) ligation during the preleukemic phase in Pax5+/- mice resulted in a significant delay of B-ALL development. These findings identify a central role for innate immunity dysregulation in B-ALL, with important implications for the understanding and potential therapeutic targeting of the preleukemic state in children.
2023-08-10 | GSE221597 | GEO
Project description:Dysregulated innate immune signaling is linked to preleukemic conditions and myeloid malignancies like MDS and AML. However, it is unknown whether sustained innate immune signaling contributes to malignant transformation. Here we show that cell-intrinsic innate immune signaling driven by miR-146a deletion (miR-146aKO), a commonly deleted gene in MDS and AML, cooperates with mutant RUNX1 (RUNX1mut) to initially induce marrow failure and features of MDS. However, miR-146aKO HSPCs expressing RUNX1mut eventually progress to a fatal AML. miR-146aKO HSPCs exhaust during serial transplantation, while expression of RUNX1mut restored their hematopoietic cell function. Thus, HSPCs exhibiting dysregulated innate immune signaling require a second hit to develop AML. Inhibiting the dysregulated innate immune pathways with a TRAF6-UBE2N inhibitor suppressed leukemic miR-146aKO/RUNX1mut HSPCs, highlighting the necessity of TRAF6-dependent cell-intrinsic innate immune signaling in initiating and maintaining AML. These findings underscore the critical role of dysregulated cell-intrinsic innate immune signaling in driving preleukemic cells toward AML progression.
2024-05-29 | GSE264052 | GEO
Project description:Dysregulated innate immune signaling is linked to preleukemic conditions and myeloid malignancies like MDS and AML. However, it is unknown whether sustained innate immune signaling contributes to malignant transformation. Here we show that cell-intrinsic innate immune signaling driven by miR-146a deletion (miR-146aKO), a commonly deleted gene in MDS and AML, cooperates with mutant RUNX1 (RUNX1mut) to initially induce marrow failure and features of MDS. However, miR-146aKO HSPCs expressing RUNX1mut eventually progress to a fatal AML. miR-146aKO HSPCs exhaust during serial transplantation, while expression of RUNX1mut restored their hematopoietic cell function. Thus, HSPCs exhibiting dysregulated innate immune signaling require a second hit to develop AML. Inhibiting the dysregulated innate immune pathways with a TRAF6-UBE2N inhibitor suppressed leukemic miR-146aKO/RUNX1mut HSPCs, highlighting the necessity of TRAF6-dependent cell-intrinsic innate immune signaling in initiating and maintaining AML. These findings underscore the critical role of dysregulated cell-intrinsic innate immune signaling in driving preleukemic cells toward AML progression.
2024-05-29 | GSE264051 | GEO
Project description:The presence of supernumerary chromosomes is the only abnormality shared by all patients diagnosed with high-hyperdiploid B cell acute lymphoblastic leukemia (HD-ALL). Despite being the most frequently diagnosed pediatric leukemia, the lack of clonal molecular lesions and complete absence of appropriate experimental models have impeded the elucidation of HD-ALL leukemogenesis. Here, we report that for 23 leukemia samples isolated from moribund Eμ-Ret mice, all were characterized by non-random chromosomal gains, involving combinations of trisomy 9, 12, 14, 15, and 17. With a median gain of three chromosomes, leukemia emerged after a prolonged latency from a preleukemic B cell precursor cell population displaying more diverse aneuploidy. Transition from preleukemia to overt disease in Eμ-Ret mice is associated with acquisition of heterogeneous genomic abnormalities affecting the expression of genes implicated in pediatric B-ALL. The development of abnormal centrosomes in parallel with aneuploidy renders both preleukemic and leukemic cells sensitive to inhibitors of centrosome clustering, enabling targeted in vivo depletion of leukemia-propagating cells. This study reveals the Eμ-Ret mouse to be a novel tool for investigating HD-ALL leukemogenesis, including supervision and selection of preleukemic aneuploid clones by the immune system and identification of vulnerabilities that could be targeted to prevent relapse.
2024-04-01 | GSE257537 | GEO
Project description:Mesenchymal niche cells may drive tissue failure and malignant transformation in the hematopoietic system but the molecular mechanisms and their relevance to human disease remain poorly defined. We demonstrated that perturbation of mesenchymal cells in a mouse model of the preleukemic disorder Shwachman-Diamond syndrome induces mitochondrial dysfunction, oxidative stress and activation of DNA damage responses in hematopoietic stem and progenitor cells. In this study we demonstrate, through massive parallel RNA sequencing of highly purified mesenchymal cells in a range of human preleukemic syndromes, TP53-S100A8/9-TLR4 inflammatory signaling as a common driving mechanism of genotoxic stress, which could be attenuated by TLR4 blockade. S100A8/9 expression in mesenchymal cells predicted outcome in myelodysplastic syndromes, the principal human preleukemic condition, independent of known prognostic variables. Collectively, findings reveal a concept of mesenchymal niche-induced genotoxic stress in heterotypic stem and progenitor cells through inflammatory signaling as an actionable determinant of disease outcome in human preleukemia. The data further provide novel conceptual and mechanistic insights into the intimate link between inflammation and cancer.
| EGAS00001001926 | EGA
Project description:Transcriptional profiling of murine cells expressing PML/RARA at the early promyelocyte stage (4 weeks old, preleukemic) and in full blown PML/RARA leukemia generated by transducing PML/RARA bone marrow with a Flt3-ITD retroviral vector Two-conditions experiment: preleukemic early promyelocytes vs leukemic promyelocytes
2015-07-15 | E-GEOD-59431 | biostudies-arrayexpress
Project description:The chimeric hematopoietic transcription factor ETV6::RUNX1 is the most common oncogenic fusion in pediatric B cell precursor acute lymphoblastic leukemia (BCP-ALL). It induces a clinically silent preleukemic state that requires secondary mutations for progression to full-blown leukemia. ETV6::RUNX1 functions primarily through repression of RUNX1 binding sites. In order to elucidate the characteristic quiescent state of ETV6::RUNX1 expressing cells, we generated preleukemic human induced pluripotent stem cell (hiPSC) models from two healthy donors using CRISPR/Cas9 gene editing. We identified upregulation of linker histone H1-0 in preleukemic hiPSCs, which was preserved upon hematopoietic differentiation and transformation to overt BCP-ALL. ETV6::RUNX1 induces activity of the H1-0 promoter whereas depletion of H1-0 specifically inhibited ETV6::RUNX1 signature genes, indicating its role as a novel key mediator of the quiescent ETV6::RUNX1 transcriptional profile. Single-cell gene expression analysis revealed that H1-0 levels strongly anti-correlate with cellular transcriptional activity, resulting in particularly high expression in quiescent cells during hematopoietic development. Pharmacologically, H1-0 protein levels correspond to susceptibility of BCP-ALL towards histone deacetylase inhibitor (HDACi) treatment and our data indicate efficacy of combinatorial drug treatment using the potent H1-0-inducing HDACi Quisinostat in BCP-ALL expressing high basal H1-0 levels.
2025-04-09 | GSE283119 | GEO
Project description:The chimeric hematopoietic transcription factor ETV6::RUNX1 is the most common oncogenic fusion in pediatric B cell precursor acute lymphoblastic leukemia (BCP-ALL). It induces a clinically silent preleukemic state that requires secondary mutations for progression to full-blown leukemia. ETV6::RUNX1 functions primarily through repression of RUNX1 binding sites. In order to elucidate the characteristic quiescent state of ETV6::RUNX1 expressing cells, we generated preleukemic human induced pluripotent stem cell (hiPSC) models from two healthy donors using CRISPR/Cas9 gene editing. We identified upregulation of linker histone H1-0 in preleukemic hiPSCs, which was preserved upon hematopoietic differentiation and transformation to overt BCP-ALL. ETV6::RUNX1 induces activity of the H1-0 promoter whereas depletion of H1-0 specifically inhibited ETV6::RUNX1 signature genes, indicating its role as a novel key mediator of the quiescent ETV6::RUNX1 transcriptional profile. Single-cell gene expression analysis revealed that H1-0 levels strongly anti-correlate with cellular transcriptional activity, resulting in particularly high expression in quiescent cells during hematopoietic development. Pharmacologically, H1-0 protein levels correspond to susceptibility of BCP-ALL towards histone deacetylase inhibitor (HDACi) treatment and our data indicate efficacy of combinatorial drug treatment using the potent H1-0-inducing HDACi Quisinostat in BCP-ALL expressing high basal H1-0 levels.
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