Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA229541 | ENA |
REPOSITORIES: ENA
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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: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: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: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.
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2012-09-11 | GSE38525 | GEO
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Project description:Hepatocellular carcinoma tumor samples were profiled for chromsomal copy number changes on Affymterix 100K SNP arrays
2012-01-19 | GSE34957 | GEO
Project description:SNP array data from 13 Brazilian childhood adrenocortical tumors (ACTs) were analyzed to detect recurrent copy number changes and highlight potential candidate driver genes.
2012-03-23 | GSE24804 | GEO
Project description:Copy number profiling of 36 ovarian tumors on Affymetrix 100K SNP arrays Thirty-six ovarian tumors were profiled for copy-number alterations with the Affymetrix 100K Mapping Array. Copy number profiling of 36 ovarian tumors on Affymetrix 500K SNP arrays Sixteen ovary tumors were profiled for copy-number alterations with the high-resolution Affymetrix 500K Mapping Array.
2010-12-16 | GSE26075 | 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