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Age and ligand specificity influence the outcome of pathogen engagement on preleukemic and leukemic B cell precursor populations.

ABSTRACT: Age and ligand specificity influence the outcome of pathogen engagement on preleukemic and leukemic B cell precursor populations.

PROVIDER: PRJNA1020909 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR26171926_1.fastq.gz	Fastqsanger.gz
	SRR26171926_2.fastq.gz	Fastqsanger.gz
	SRR26171927_1.fastq.gz	Fastqsanger.gz
	SRR26171927_2.fastq.gz	Fastqsanger.gz
	SRR26171928_1.fastq.gz	Fastqsanger.gz

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Age and ligand specificity influence the outcome of pathogen engagement on preleukemic and leukemic B cell precursor populations.

Project description:Common infections have long been proposed to play a role in the development of pediatric B cell acute lymphoblastic leukemia (B-ALL). However, epidemiological studies report contradictory effects of infection exposure on subsequent B-ALL risk, and no specific pathogen has been definitively linked to the disease. A unifying mechanism to explain the divergent outcomes could inform disease prevention strategies. We previously reported that the pattern recognition receptor (PRR) ligand Poly(I:C) exerted effects on B-ALL cells that were distinct from those observed with other nucleic acid-based PRR ligands. Here, using multiple double-stranded RNA moieties, we show that the overall outcome of exposure to Poly(I:C) reflects the balance of opposing responses induced by its ligation to endosomal and cytoplasmic receptors. This PRR response biology is shared between mouse and human B-ALL and increases leukemia-initiating cell burden in vivo during the preleukemia phase of B-ALL, primarily through TNF-a signaling. The age of the responding immune system further influences the impact of dsRNA exposure on B-ALL cells in both mouse and human settings. Overall, our study demonstrates that potentially pro- and anti-leukemic effects can each be generated by stimulation of pathogen recognition pathways and indicates a mechanistic explanation for the contrasting epidemiologic associations reported for infection exposure and B-ALL.

2023-12-13 | GSE244018 | GEO

Age and ligand specificity influence the outcome of pathogen engagement on preleukemic and leukemic B-cell precursor populations.

Project description: Not available

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Effect of PML/RARA on the transcriptome of preleukemic early promyelocytes vs PML/RARA-Flt3ITD leukemic promyelocytes

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

Immune stress suppresses innate immune signaling in preleukemic precursor B cells to cause leukemia

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.

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pre-B cells from normal control, preleukemic, fully leukemic and fully leukemic, nilotinib-treated P190 BCR/ABL transgenic mice

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LMO2 expression in HSCs causes T-ALL in the presence of an intact thymic niche [preleukemic and leukemic cells]

Project description:We used microarrays to investigate gene expression changes in tumor-bearing Sca1-TOMATO-Lmo2 mice and in preleukemic cells from Sca1-TOMATO-Lmo2 mice. Tumor-bearing thymus of eleven Sca1-TOMATO-Lmo2 mice compared with thymus cells from 4 WT mice, with TOMATO-positive thymus preleukemic T cells from 5 Sca1-TOMATO-Lmo2 mice and with TOMATO-negative thymus preleukemic T cells from 5 Sca1-TOMATO-Lmo2 mice GSM2209749 - GSM220975 and GSM2209757 - GSM2209759 were re-analyzed by GSE83571 (GSM2209767 - GSM2209776).

2016-06-22 | E-GEOD-83570 | biostudies-arrayexpress

LMO2 expression in HSCs causes T-ALL in the presence of an intact thymic niche [preleukemic and leukemic cells]

Project description:We used microarrays to investigate gene expression changes in tumor-bearing Sca1-TOMATO-Lmo2 mice and in preleukemic cells from Sca1-TOMATO-Lmo2 mice.

2016-06-22 | GSE83570 | GEO

Effect of PML/RARA on the transcriptome of preleukemic early promyelocytes vs PML/RARA-Flt3ITD leukemic promyelocytes

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PAX5-Inherited susceptibility causes leukemia by conferring sensitivity to DNA damage in preleukemic B cells

Project description:We used microarrays to analyze gene expression changes in leukemic bone marrow cells from Pax5+/- and WT mice, comparing them with preleukemic bone marrow precursor B cells from both genotypes. All mice were exposed to a single low-dose irradiation (2 Gy). PAX5 is a master regulator of B-cell development, and germline mutations in PAX5 predispose individuals to B-cell acute lymphoblastic leukemia (B-ALL). While PAX5 alterations are a hallmark of B-ALL, the mechanisms linking inherited susceptibility to leukemic transformation remain poorly understood. Here, we provide in vivo genetic evidence demonstrating that reduced Pax5 dosage increases sensitivity to DNA damage, acting as a key factor in B-ALL initiation. Using a mouse model of Pax5 heterozygosity, we show that exposure to a single low-dose irradiation (2 Gy) significantly accelerates leukemia onset, establishing a direct link between genetic predisposition and environmental stress. Notably, the resulting murine B-ALLs closely resemble the human disease, exhibiting complete Pax5 loss, CD19 downregulation, and a high incidence of DNA double-strand breaks. Mechanistically, we identify Pax5 as a regulator of p53-mediated DNA damage responses in preleukemic B cells, highlighting its role beyond lineage specification. These findings provide a mechanistic framework for the interplay between PAX5 deficiency, genomic instability, and environmental factors in early B-ALL development, uncovering new potential vulnerabilities for therapeutic intervention.

2025-03-19 | GSE291995 | GEO

Inflammatory Signaling Pathways in Preleukemic and Leukemic Stem Cells.

Project description: Not available

| S-EPMC5693908 | biostudies-literature