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

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

PROVIDER: PRJNA1236298 | ENA |

REPOSITORIES: ENA

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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

Pax5 drives the metabolic shift in the development of pB-ALL as a result of BCR/ABLp190 susceptibility

Project description:We used microarrays to investigate gene expression changes in tumor-bearing Sca1-BCR/ABLp190 and Sca1-BCR/ABLp190+Pax5+/- mice. We also analyze gene expression changes in preleukemic Sca1-BCR/ABLp190 and Sca1-BCR/ABLp190+Pax5+/- mice

2016-08-16 | GSE85600 | GEO

Inhibition of Inflammatory Signaling in Pax5 Mutant Cells Mitigates B-cell leukemogenesis against leukemia

Project description:We used microarrays to investigate gene expression changes in healthy and leukemic cells from Pax5+/- and IL6+/-;Pax5+/- mice in CF and SPF housing conditions. PAX5 is one of the most frequently mutated genes in B-cell acute lymphoblastic leukemia (B-ALL), and children with inherited preleukemic PAX5 mutations are at a higher risk of developing the disease. Abnormal profiles of inflammatory markers can be detected in neonatal blood spot samples of children who later developed B-cell precursor B-ALL. However, how inflammatory signals contribute to B-ALL development is unclear. Here, we demonstrate that Pax5 loss results in the enhanced production of the inflammatory cytokine interleukin-6 (IL-6), which appears to act in an autocrine fashion to promote leukemia growth. In vivo genetic downregulation of IL-6 in Pax5 mutant mice retards B-cell leukemogenesis. In vivo pharmacologic inhibition of IL-6 with a neutralizing IL-6 antibody in Pax5 mutant mice with B-ALL clears leukemic cells. This exciting novel IL 6 signaling paradigm identified in mice was also substantiated in humans. Altogether, our studies establish aberrant IL6 expression caused by Pax5 loss as a hallmark of Pax5-dependent B-ALL and the IL6 as a therapeutic vulnerability for B-ALL characterized by PAX5 loss.

2020-07-17 | GSE154589 | GEO

Infection exposure is a causal factor in B-precursor acute lymphoblastic leukemia as a result of Pax5 inherited susceptibility

Project description:We used microarrays to investigate gene expression changes in tumor-bearing Pax5+/- mice Tumor-bearing bone marrows of three Pax5+/- mice compared with B220+ bone marrow B cells from five WT mice

2014-10-21 | E-GEOD-62529 | 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.

2023-08-10 | GSE221597 | GEO

Reduction in Pax5 activity drives ionizing radiation-mediated B-cell acute lymphoblastic leukemia development by modulating DNA-damage response

Project description:We used microarrays to investigate gene expression changes in tumor-bearing Pax5+/- IR and WT-IR mice. We also analyze gene expression changes in preleukemic Pax5+/- IR and WT-IR mice

2019-05-04 | GSE130667 | GEO

Infection exposure is a causal factor in B-precursor acute lymphoblastic leukemia as a result of Pax5 inherited susceptibility

Project description:We used microarrays to investigate gene expression changes in tumor-bearing Pax5+/- mice

2014-10-21 | GSE62529 | GEO

Germline Aberrations of PAX5 Cause Susceptibility to pre-B cell Acute Lymphoblastic Leukemia

Project description:A novel heterozygous germline variant, c.547G>A (p.Gly183Ser), in the paired box protein encoding gene, PAX5, was found to segregate with disease in two unrelated kindreds with autosomal dominant pre-B cell acute lymphoblastic leukemia (ALL). Leukemic cells from both families exhibited 9p deletion, with loss-of-heterozygosity and retention of the mutant PAX5 allele at 9p13. Two additional sporadic ALL cases with 9p loss demonstrated PAX5 Gly183 substitution in the leukemic cells. Functional and gene expression analysis of the PAX5 germline variants demonstrated reduced transcriptional activity. These data extend the role of PAX5 alterations in the pathogenesis of pre-B ALL, and implicate PAX5 in a novel syndrome of germline susceptibility to pre-B cell neoplasia. We analyzed 40 samples comprising sevenfold replicates of transductions with empty vector, wild type PAX5 and 4 mutant PAX5 constructs

2013-08-01 | E-GEOD-45260 | biostudies-arrayexpress

Germline Aberrations of PAX5 Cause Susceptibility to pre-B cell Acute Lymphoblastic Leukemia

Project description:A novel heterozygous germline variant, c.547G>A (p.Gly183Ser), in the paired box protein encoding gene, PAX5, was found to segregate with disease in two unrelated kindreds with autosomal dominant pre-B cell acute lymphoblastic leukemia (ALL). Leukemic cells from both families exhibited 9p deletion, with loss-of-heterozygosity and retention of the mutant PAX5 allele at 9p13. Two additional sporadic ALL cases with 9p loss demonstrated PAX5 Gly183 substitution in the leukemic cells. Functional and gene expression analysis of the PAX5 germline variants demonstrated reduced transcriptional activity. These data extend the role of PAX5 alterations in the pathogenesis of pre-B ALL, and implicate PAX5 in a novel syndrome of germline susceptibility to pre-B cell neoplasia. We analyzed 10 samples of J558 murine myeloma cells infected with MSCV-Puro-IRES-GFP (PIG) empty vector (EV; three independent replicates), MSCV-PIG Pax5 WT (WT; three independent replicates), and MSCV-PIG Pax5 G183S (Mut; four independent replicates). Cells were selected with puromycin after infection for 5-7 days, subsequently cells were sorted for GFP and IgM expression by FACS.

2014-04-06 | E-GEOD-45834 | biostudies-arrayexpress

Gene expression in 832/13 INS1 beta-cells transduced with lentiviral vector conferring expression of GFP or Pax5

Project description:We found PAX5 to be overexpressed in human pancreatic islets of donors from donors with type 2 diabetes compared to islets from non-diabetic individuals. Functional follow-up showed that Pax5 overexpression in rat clonal beta-cells (832/13 INS1) results in impaired insulin secretion. Microarrays were used to investigate if overexpression of Pax5 alters the gene expression profile of 832/13 INS1 beta-cells.

2023-01-11 | GSE211310 | GEO

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