Ontology highlight
ABSTRACT:
PROVIDER: PRJNA229540 | ENA |
REPOSITORIES: ENA
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Project description:Data from "Direct and indirect targets of the E2A-PBX1 leukemia-specific fusion protein" to be published in PLOS One, authors Christofer Diakos, Yuanyuan Xiao, Shichun Zheng, Leo Kager, Michael Dworzak, Joseph L. Wiemels The experiment showed direct targets of the fusion protein. In the manuscript, individual gene targets are explained, along with DNA motifs that the fusion protein bound to. Demonstrates the "direct" targets of the E2A-PBX1 leukemia fusion protein, which is a feature of about 5% of all chilldhood leukemia.
2013-11-23 | GSE52653 | GEO
Project description:Data from "Direct and indirect targets of the E2A-PBX1 leukemia-specific fusion protein" to be published in PLOS One, authors Christofer Diakos, Yuanyuan Xiao, Shichun Zheng, Leo Kager, Michael Dworzak, Joseph L. Wiemels The experiment showed direct targets of the fusion protein. In the manuscript, individual gene targets are explained, along with DNA motifs that the fusion protein bound to. Demonstrates the "direct" targets of the E2A-PBX1 leukemia fusion protein, which is a feature of about 5% of all chilldhood leukemia. Comparison of the ChIP pull-down from E2A antibody in an E2A-PBX1 positive cell line, compared to the input DNA. There are 3 replicate experiments
2013-11-23 | E-GEOD-52653 | biostudies-arrayexpress
Project description:The experiment was to detect the identity and range of copy number alterations in a subtype of childhood leukemia defined by t(1;19) translocaitons The data will be presented in the manuscript "Direct and indirect targets of the E2A-PBX1 leukemia-specific fusion protein" to be published in PLOS One, authors Christofer Diakos, Yuanyuan Xiao, Shichun Zheng, Leo Kager, Michael Dworzak, Joseph L. Wiemels
2013-11-23 | GSE52654 | GEO
Project description:The experiment was to detect the identity and range of copy number alterations in a subtype of childhood leukemia defined by t(1;19) translocaitons The data will be presented in the manuscript "Direct and indirect targets of the E2A-PBX1 leukemia-specific fusion protein" to be published in PLOS One, authors Christofer Diakos, Yuanyuan Xiao, Shichun Zheng, Leo Kager, Michael Dworzak, Joseph L. Wiemels A series of leukemia DNAs were subjected to Affymetrix SNP 5.0 (Nsp) arrays
2013-11-23 | E-GEOD-52654 | biostudies-arrayexpress
Project description:E2A, a basic helix-loop-helix (bHLH) transcription factor, plays a crucial role in determining tissue-specific cell fate, including differentiation of B cell lineages. In 5% of childhood acute lymphoblastic leukemia (ALL), the t(1,19) chromosomal translocation specifically targets the E2A gene and produces an oncogenic E2A-PBX1 fusion protein. While previous studies have demonstrated oncogenic functions of E2A-PBX1 in cell and animal models, the E2A-PBX1-enforced cistrome, the E2A-PBX1 interactome, and related mechanisms underlying leukemogenesis remain unclear. Here, by unbiased genomic profiling approaches, we identify the direct target sites of E2A-PBX1 in t(1,19)-positive pre-B ALL cells and show that, compared to normal E2A, E2A-PBX1 preferentially binds to a subset of gene loci co-bound by RUNX1 and gene-activating machineries (p300, MED1, and H3K27 acetylation). Using biochemical analyses, we further document a direct interaction between E2A-PBX1 and RUNX1 and show that E2A-PBX1 binding to gene enhancers is dependent on RUNX1, but not the DNA-binding activity harbored within the PBX1 homeodomain of E2A-PBX1. Transcriptome analyses and cell transformation assays further establish a significant RUNX1 requirement for E2A-PBX1-mediated target gene activation and leukemogenesis. Notably, the RUNX1 locus itself is also directly activated by E2A-PBX1, indicating a multilayered interplay between E2A-PBX1 and RUNX1. Collectively, our study provides the first unbiased profiling of the E2A-PBX1 cistrome in pre-B ALL cells and reveals a previously unappreciated pathway in which E2A-PBX1 acts in concert with RUNX1 to enforce transcriptome alterations for the development of pre-B ALL.
2020-03-06 | GSE138031 | GEO
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
Project description:Despite improved 5-year overall survival rates in B-cell acute lymphoblastic leukemia (B-ALL) due to therapy escalation, effective treatments for relapsed and treatment-resistant disease, especially in specific subtypes like those with TCF3 (formerly E2A) fusions, remain scarce. TCF3, a key regulator of B-cell development, is implicated in various chromosomal translocations linked to lymphoid malignancies, such as TCF3::PBX1 fusion (5% of pediatric B-ALL) and TCF3::HLF fusion (~0.5% of pediatric B-ALL). Current omics research predominantly relies on transcriptomics, but it's increasingly recognized that this may not adequately reflect protein expression, the main targets of drugs and functional entities in biological processes. This study comprehensively analyzed proteomic landscapes of TCF3::HLF+ (n=6) and TCF3::PBX1+ (n=5) B-ALL using primary patient-derived xenografts (PDX), liquid chromatography tandem mass spectrometry, and data-dependent acquisition.
2024-07-05 | PXD053677 | Pride
Project description:We used ChIPseq in primary pre-B acute lymphomablastic leukemia (ALL) cells to identify target genes of the oncogenes TCF3-PBX1 and BCL6 that are involved in leukemogenesis of TCF3-PBX1 pre-B ALL. ChIP-seq using E2A (TCF3), PBX1, p300 and BCL6 antibodies in ICN12 cells (primary pre-B acute lymphomablastic leukemia)
2015-02-08 | E-GEOD-59538 | biostudies-arrayexpress
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
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