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Pre-B cell leukemia homeobox protein Pbx1 is associated with lupus susceptibility in mice and humans

ABSTRACT: Sle1a.1 is part of the Sle1a lupus susceptibility locus which results in the production of activated and autoreactive CD4+ T cells as well as a reduction in the peripheral regulatory T cell (Treg) pool. Sle1a.1 CD4+ T cells showed a defective response to retinoic acid (RA) expansion of TGFβ-induced Tregs. At the molecular level, Sle1a.1 corresponds to an increased expression of a novel splice isoform of Pbx1, Pbx1-d. Pbx1-d over-expression is sufficient to induce an activated/inflammatory phenotype in Jurkat T cells, and to decrease their apoptotic response to RA. PBX1-d is expressed more frequently in lupus patients than in healthy controls, and its presence correlates with an increased memory T cell population. These findings indicate that Pbx1 is a novel lupus susceptibility gene that regulates T cell activation and tolerance.

ORGANISM(S): Mus musculus

PROVIDER: GSE22313 | GEO | 2010/06/16

SECONDARY ACCESSION(S): PRJNA127379

REPOSITORIES: GEO

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Pre-B cell leukemia homeobox protein Pbx1 is associated with lupus susceptibility in mice and humans

Project description:Sle1a.1 is part of the Sle1a lupus susceptibility locus which results in the production of activated and autoreactive CD4+ T cells as well as a reduction in the peripheral regulatory T cell (Treg) pool. Sle1a.1 CD4+ T cells showed a defective response to retinoic acid (RA) expansion of TGFÎ²-induced Tregs. At the molecular level, Sle1a.1 corresponds to an increased expression of a novel splice isoform of Pbx1, Pbx1-d. Pbx1-d over-expression is sufficient to induce an activated/inflammatory phenotype in Jurkat T cells, and to decrease their apoptotic response to RA. PBX1-d is expressed more frequently in lupus patients than in healthy controls, and its presence correlates with an increased memory T cell population. These findings indicate that Pbx1 is a novel lupus susceptibility gene that regulates T cell activation and tolerance. Total RNA from CD4+ T cells from C57BL/6 (B6) and B6.Sle1a.1 (Sle) mice was isolated, with 4 biological replicates each. Gene expression data from C57BL/6 mice were compared with data from B6.Sle2c1 mice.

2010-07-08 | E-GEOD-22313 | biostudies-arrayexpress

Pbx1-d Induces T cell Activation and a Decreased Apoptosis in Response to Retinoic Acids (RA)

2010-07-07 | GSE22799 | GEO

Pbx1-d Induces T cell Activation and a Decreased Apoptosis in Response to Retinoic Acids (RA)

Project description:The hypothesis was tested that the Pbx1-d isoform was responsible for the Sle1a.1 phenotypes in CD4+ T cells. Jurkat T cells were transfected with a lentiviral construct expressing Pbx1-d-GFP or control RFP. Pbx1-d over-expression reduced the percentage of late apoptotic cells in response to anti-CD3 and anti-CD28 stimulation as compared with control-Lin28-transfected cells. Overall, these data demonstrate that over-expression of Pbx1-d results in an activated/inflammatory phenotype and in a defective response to RA in Jurkat T cells, strongly suggesting that the increased expression of Pbx1-d is responsible for the Sle1a.1 phenotypes. Jurkat T cells (5 x 105 cells/ml) were transfected with an lentiviral (LV) vector expressing either control (RFP or Lin28) or Pbx1-d-GFP. Total RNA was extracted from GFP+ or RFP+ FACS-sorted Jurkat T cells transfected LV-GFP-Pbx1-d or LV-RFP, as well as non-transfected cells in 4 independent transfections per group.

2010-07-07 | E-GEOD-22799 | biostudies-arrayexpress

Microarray data of mouse primary E2A-PBX1 leukemia and preleukemia cells

Project description:Microarray data of mouse primary E2A-PBX1 leukemias and preleukemia cells were compared to wild-type B-cell progenitor cells Aberrant activation of signaling pathways has been linked to leukemogenesis, however, little is known about cell signaling perturbations induced by fusion transcription factors. To address this, we interrogated activated signaling pathways in a comparative analysis of mouse and human leukemias expressing the chimeric fusion protein E2A-PBX1, which is present in 5-7% of pediatric and 50% of pre-B-cell receptor (preBCR+) ALL. We describe here signaling network remodeling by E2A-PBX1 in pre-B-ALL, which results in hyperactivation of PLCγ2. Depletion of PLCγ2 reduced proliferation of mouse and human ALLs, including E2A-PBX1 leukemias, and increased disease-free survival after secondary transplantation. E2A-PBX1 binds and activates the transcription of its target genes ZAP70, SYK and LCK, which encode kinases upstream of PLCγ2. Efficient shRNA-mediated depletion of the respective upstream kinases decreased cell proliferation and phosphorylated levels of PLCγ2 (pPLCγ2). Pairwise compound knockdown of ZAP70, SYK or LCK showed additive effects on cell growth inhibition, providing a rationale for combination therapy. Inhibition of SYK, LCK and SFK with small molecule inhibitors, including dasatinib, was highly effective in reducing pPLCγ2 and inhibiting proliferation of preBCR+ leukemias in vitro and in vivo. Combination small molecule inhibition of SYK, LCK and SFK showed promising preclinical efficacy for preBCR+/E2A-PBX1+ leukemias. These studies demonstrate that E2A-PBX1 induces signaling pathway perturbations upstream of PLCγ2, which render leukemias amenable to targeted therapeutic inhibition.

2016-05-03 | GSE81010 | GEO

INTEGRATED MULTI-OMICS ANALYSIS OF PBX1 IN MOUSE ADULT NEURAL STEMAND PROGENITOR CELLS IDENTIFIES A TRANSCRIPTIONAL MODULE WITH RELEVANCE TO LEUKEMOGENESIS

Project description:Developmental transcription factors act in networks, but how these networks achieve cell- and tissue specificity is still poorly understood. We here explored pre-B-cell leukemia homeobox 1 (PBX1) in adult neurogenesis combining genomic, transcriptomic, and proteomic approaches. ChIP-Seq analysis uncovered PBX1 binding to a wide range of different genes. Integration of PBX1 ChIP-seq with ATAC-seq data predicted interaction partners, which were subsequently validated by mass-spectrometry. Spatial transcriptomics revealed distinct temporal expression dynamics of Pbx1 and interacting factors. Among these were class I bHLH proteins TCF3, TCF4 and TCF12. RNA-seq upon Pbx1, Tcf3 and Tcf4 knockdown identified proliferation and differentiation associated genes as shared targets. Neuronal differentiation was reduced upon depletion of either factor, suggesting functional cooperation between PBX1 and TCF3/4. Notably, while physiological PBX1-TCF interactions have not yet been described, chromosomal translocation resulting in genomic TCF3::PBX1 fusion characterizes a subtype of acute lymphoblastic leukemia. Introducing Pbx1 into Nalm6 cells, a pre B-cell line expressing TCF3 but lacking PBX1, upregulated leukemogenic genes including BLK and NOTCH3, arguing that functional PBX1-TCF cooperation likely extends to hematopoietic contexts. Our study hence uncovers a PBX1-TCF module orchestrating the balance between progenitor cell proliferation and differentiation in adult neurogenesis with implications for leukemia etiology.

2024-09-16 | PXD048222 | Pride

Pbx1 expression is required for myeloproliferative neoplasm onset and maintenance

Project description:Pre B cell leukemia homeobox 1 (Pbx1) regulates the balance between self-renewal and differentiation of hematopoietic stem cells, and maintains proto-oncogenic transcriptional pathways implicated in several tumors. Its aberrant expression was found in a subset of myeloproliferative neoplasms (MPN) patients bearing the JAK2V617F mutation. To investigate if Pbx1 contributes to MPN, and to explore its potential as therapeutic target, we generated a new mouse strain, that we called JP, by crossing a known JAK2V617F inducible knock-in MPN model with a Pbx1 conditional-ko. In JP mice we can simultaneously activate the human JAK2 mutation and delete Pbx1. Typical MPN features, such as thrombocytemia and granulocytosis, did not develop in the absence of Pbx1. Erythrocytosis, initially displayed by JP mice, gradually resolved over time. Moreover, splenic myeloid metaplasia and in vitro cytokine independent growth were rescued by Pbx1 inactivation. Through RNA-Sequencing we analyzed molecular pathways downstream of Pbx1 and involved in MPN maintenance in stem and progenitor cells. The aberrant transcriptome in the MPN model compared to wild-type was rescued by the absence of Pbx1. Our results demonstrate that inhibition of the Pbx1-driven transcriptional program is beneficial in MPN. Modulation of Pbx1 activity by direct targeting or by targeting its downstream mediators might thus represent a novel therapeutic approach.

2021-10-21 | GSE153482 | GEO

Targeting TNF/IL-17/MAPK Pathway in hE2A-PBX1 Leukemia: effects of OUL35, KJ-Pyr-9, and CID44216842

Project description:t(1;19)(q23;p13) is one of the most common translocation genes in childhood acute lymphoblastic leukemia (ALL) and is also present in acute myeloid leukemia (AML) and mixed-phenotype acute leukemia (MPAL). This translocation results in the formation of the oncogenic E2A-PBX1 fusion protein, which contains a trans-activating domain from E2A and a DNA-binding homologous domain from PBX1. Despite its clear oncogenic potential, the pathogenesis of E2A-PBX1 fusion protein is not fully understood (especially in leukemias other than ALL), and effective targeted clinical therapies have not been developed. To address this, we established a stable and heritable zebrafish line expressing human E2A-PBX1 (hE2A-PBX1) for high-throughput drug screening. Blood phenotype analysis showed that hE2A-PBX1 expression induced myeloid hyperplasia by increasing myeloid differentiation propensity of hematopoietic stem cells (HSPCs) and myeloid proliferation in larvae, and progressed to AML in adults. Mechanistic studies revealed that hE2A-PBX1 activated the TNF/IL-17/MAPK signaling pathway in blood cells and induced myeloid hyperplasia by up-regulating the expression of the runx1. Interestingly, through high-throughput drug screening, three small molecules targeting the TNF/IL-17/MAPK signaling pathway were identified, including OUL35, KJ-Pyr-9, and CID44216842, which not only alleviated the hE2A-PBX1-induced myeloid hyperplasia in zebrafish but also inhibited the growth and oncogenicity of human pre-B ALL cells with E2A-PBX1. Overall, this study provides a novel hE2A-PBX1 transgenic zebrafish leukemia model and identifies potential targeted therapeutic drugs, which may offer new insights into the treatment of E2A-PBX1 leukemia and improve the quality of life of leukemia patients.

2024-07-10 | GSE234222 | GEO

Effect of overexpression PBX1 on gene expression in HCT116 cells

Project description:To investigate the function of PBX1 in colorectal cancer (CRC). We overexpressed the PBX1 in CRC cell lines HCT116 with plasmids.

2023-01-31 | GSE218378 | GEO

The transcription factor PBX1 drives natural killer cells to promote fetal development

Project description:Perfect fetal development is a solid foundation for successful fertility, in which the abundant natural killer (NK) cells in the decidua tissue at the maternal-fetal interface play an important role during the first trimester. The functional subsets and transcriptional regulation mechanisms of decidual NK (dNK) cells remain poorly understood. Here, we identified CD49a+PBX1+ dNK cells as a unique subset of NK cells that promote fetal development in both human and mice. PBX1 drove the transcription of key functional molecules pleiotrophin and osteoglycin that promote fetal development through direct promoter binding. In patients with unexplained recurrent spontaneous abortion (URSA), decreased expression of PBX1 and PBX1(G21S) mutation correlated with fetal growth restriction and pregnancy failure. Inactivation of Pbx1 in mouse NK cells caused impaired fetal development due to a decrease in growth promoting factors. Our observations reveal the molecular regulation mechanism of CD49a+PBX1+ dNK cells promoting fetal development, and indicate that impaired PBX1 in dNK cells may serve as pathogenesis and biomarker of URSA.

2021-01-01 | GSE110244 | GEO

Functional assessment of a new PBX1 variant through CRISPR-Cas9 gene editing

Project description:To assess the role of a variant of unknown significance in PBX1 (p.(Arg107Gln) by generating a HEK293T-derived cell line knockdown for PBX1 (clone 22 cells) through CRISPR-Cas9. We then transfected the KD cells or the WT HEK293T cells with a plasmid encoding either WT or Arg107Gln PBX1 proteins.

2023-02-28 | GSE215967 | GEO

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