In Vitro Transformation of Primary Human CD34+ Cells by AML Fusion Oncogenes: Early Gene Expression Profiling Reveals Possible Drug Target in AML
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE57194 | GEO | 2014/05/01
SECONDARY ACCESSION(S): PRJNA245884
REPOSITORIES: GEO
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Project description:Different fusion oncogenes in acute myeloid leukemia (AML) have distinct clinical and laboratory features suggesting different modes of malignant transformation. Here we compare the in vitro effects of representatives of major groups of AML fusion oncogenes on primary human CD34+ cells. For the 3 d and 8 d time points, the oncogenes were retrovirally expressed in primary human CD34+ cells, with cells transduced with empty retroviral vector as controls. As retroviral transduction requires days, for the 6 h time point the oncogenes were expressed from a pTracer-CMV/Bsd plasmid using nucleofection. Cells nucleofected with empty pTracer-CMV/Bsd vector were used as a control.
2014-05-01 | E-GEOD-57194 | biostudies-arrayexpress
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Project description:Exposure to ionizing radiation during childhood markedly increases the risk of developing papillary thyroid cancer. We identified non-overlapping somatic driver mutations in all 26 cases of post-Chernobyl thyroid cancers we studied through candidate gene assays and next generation RNA-sequencing. We found that 22/26 harbored fusion oncogenes arising primarily through intrachromosomal rearrangements. Altogether 23/26 of the oncogenic drivers identified in this cohort aberrantly activate MAPK signaling, including the two novel somatic rearrangements ETV6-NTRK3 and AGK-BRAF. Two other tumors harbored distinct fusions leading to overexpression of the nuclear receptor PPARγ. A lower prevalence of fusion oncogenes was found in a cohort of pediatric thyroid cancers from children from the same geographical regions that were not exposed to radiation. Radiation-induced thyroid cancers are a paradigm of tumorigenesis driven by fusion oncogenes that activate MAPK signaling or, less frequently, a PPARγ-driven transcriptional program. Examination of transcriptome profiles and genetic somatic changes in thyroid cancer.
2013-10-25 | E-GEOD-48850 | biostudies-arrayexpress
Project description:Exposure to ionizing radiation during childhood markedly increases the risk of developing papillary thyroid cancer. We identified non-overlapping somatic driver mutations in all 26 cases of post-Chernobyl thyroid cancers we studied through candidate gene assays and next generation RNA-sequencing. We found that 22/26 harbored fusion oncogenes arising primarily through intrachromosomal rearrangements. Altogether 23/26 of the oncogenic drivers identified in this cohort aberrantly activate MAPK signaling, including the two novel somatic rearrangements ETV6-NTRK3 and AGK-BRAF. Two other tumors harbored distinct fusions leading to overexpression of the nuclear receptor PPARγ. A lower prevalence of fusion oncogenes was found in a cohort of pediatric thyroid cancers from children from the same geographical regions that were not exposed to radiation. Radiation-induced thyroid cancers are a paradigm of tumorigenesis driven by fusion oncogenes that activate MAPK signaling or, less frequently, a PPARγ-driven transcriptional program.
2013-10-25 | GSE48850 | GEO
Project description:The label-free quantitative proteome was generated for 42 primary AML patient samples enriched for CD34+ cells (or mononuclear cells in the case of NPMcyt sameples) and as controls 6 mobilized peripheral blood CD34+ cells were included. Furthermore, 6 AML cell lines were included, and also primary mesenchymal stem cells grown under normaoxia or hypoxia were included.
2022-03-15 | PXD030463 | Pride
Project description:The BET (bromodomain and extra terminal) protein family members including BRD4 bind to acetylated lysines on histones and regulate the expression of important oncogenes, e.g., MYC and BCL2. Here we demonstrate the sensitizing effects of the histone hyperacetylation inducing pan-histone deacetylase inhibitor (HDI) panobinostat (PS) on human AML blast progenitor cells (BPCs) to the BET protein inhibitor JQ1. Treatment with JQ1 but not its inactive enantiomer (R-JQ1) was highly lethal against AML BPCs expressing mutant NPM1c+ with or without co-expression of FLT3-ITD, or AML expressing MLL fusion oncoprotein. JQ1 treatment reduced binding of BRD4 and RNA polymerase II to the DNA of MYC and BCL2, and reduced their levels in the AML cells. Co-treatment with JQ1 and the HDAC inhibitor panobinostat (PS) synergistically induced apoptosis of the AML BPCs, but not of normal CD34+ hematopoietic progenitor cells. This was associated with greater attenuation of MYC and BCL2, while increasing p21, BIM and cleaved PARP levels in the AML BPCs. Co-treatment with JQ1 and PS significantly improved the survival of the NOD/SCID mice engrafted with OCI-AML3 or MOLM13 cells (p < 0.01). These findings highlight co-treatment with a BRD4 antagonist and an HDI as a potentially efficacious therapy of AML. Two samples were analyzed (untreated cells, cells treated with JQ1)
2014-01-01 | E-GEOD-51950 | biostudies-arrayexpress
Project description:Purpose: To investigate whether human cord blood CD34+ hematopoietic stem and progenitor cells (CB HSPCs) transduced with CBFA2T3-GLIS2 (C/G) expression construct recapitulates primary C/G acute myeloid leukemia (AML). Methods: CB HSPCs were transduced with either C/G fusion/GFP or GFP control contruct (C/G-CB or GFP-CB cells, respectively) and cultured in endothelial cell (EC) co-culture or myeloid promoting culture (MC) for 12 weeks. RNA from transduced cells were isolated at week 1, 6 and 12 in either culture condition. Whole transcriptome RNA-sequencing was conducted using 75bp strand-specific paired-end mRNA libraries and sequenced on the Illumina HiSeq 2000/2500. Results: Unsurpervised clustering analysis of RNA-sequencing of C/G-CB cells cultured with ECs or in MC demonstrated that the C/G-CB cells from weeks 6 and 12 in EC co-culture clustered with primary C/G-positive patient samples, but not C/G-CB cells cultured in MC nor GFP controls. In addition, EC C/G-CB cells had signficant enrichemnt of WNT, HEDGEHOG and TGF-beta pathways. However, both EC and MC cultures revealed up-regulation of ERG and BMP2, genes compared to GFP control, which are genes previously shown to be strongly upregulated in C/G AML, and concomitant down-regulation of the erythroid-megakaryocyte differentiation gene GATA1. Conclusions: We find that lentiviral transduction of C/G fusion is sufficient to induce malignant transformation of human CB HSPCs that recapitulates the transcriptome of primary C/G AML.
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Project description:Whole exome sequencing analysis of mouse AML with MLL AF9 fusion gene
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Project description:The BET (bromodomain and extra terminal) protein family members including BRD4 bind to acetylated lysines on histones and regulate the expression of important oncogenes, e.g., MYC and BCL2. Here we demonstrate the sensitizing effects of the histone hyperacetylation inducing pan-histone deacetylase inhibitor (HDI) panobinostat (PS) on human AML blast progenitor cells (BPCs) to the BET protein inhibitor JQ1. Treatment with JQ1 but not its inactive enantiomer (R-JQ1) was highly lethal against AML BPCs expressing mutant NPM1c+ with or without co-expression of FLT3-ITD, or AML expressing MLL fusion oncoprotein. JQ1 treatment reduced binding of BRD4 and RNA polymerase II to the DNA of MYC and BCL2, and reduced their levels in the AML cells. Co-treatment with JQ1 and the HDAC inhibitor panobinostat (PS) synergistically induced apoptosis of the AML BPCs, but not of normal CD34+ hematopoietic progenitor cells. This was associated with greater attenuation of MYC and BCL2, while increasing p21, BIM and cleaved PARP levels in the AML BPCs. Co-treatment with JQ1 and PS significantly improved the survival of the NOD/SCID mice engrafted with OCI-AML3 or MOLM13 cells (p < 0.01). These findings highlight co-treatment with a BRD4 antagonist and an HDI as a potentially efficacious therapy of AML.
2014-01-01 | GSE51950 | GEO
Project description:Microarray-based classifiers and prognosis models identify subgroups with distinct clinical outcomes and high risk of AML transformation of myelodysplastic syndrome (MDS) An array-based Diagnostic Classifier (DC) model, developed for and evaluated during the MILE study, correctly identified ~50% of the unfractionated MDS specimens submitted to the study; predictions for the other samples were split between “none-of-the-targets” classes and AML signatures, but this distinction also reflected clinical outcome in terms of time to AML transformation. Furthermore, an improved Prognostic Classifier (PC) model was developed that correlated with both time to AML transformation and overall survival. Keywords: Microarray-based gene expression profiling aimed at prediction of AML transformation in MDS
2009-06-09 | GSE15061 | GEO