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St. Jude Children's Research Hospital - Washington University Pediatric Cancer Genome Project (PCGP): Somatic Mutations in Pediatric AML FAB-M7 Subtype by Whole Transcriptome Sequencing

ABSTRACT: St. Jude Children's Research Hospital - Washington University Pediatric Cancer Genome Project (PCGP): Somatic Mutations in Pediatric AML FAB-M7 Subtype by Whole Transcriptome Sequencing

PROVIDER: PRJNA75335 | ENA |

REPOSITORIES: ENA

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St. Jude Children's Research Hospital - Washington University Pediatric Cancer Genome Project(PCGP): Whole Genome Sequencing of Childhood Medulloblastoma

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Transcriptome Sequencing of Pediatric AML FAB-M7

Project description:<p>High resolution analysis of DNA copy number abnormalities and loss-of-heterozygosity on acute myeloblastic leukemia samples utilizing SNP arrays has demonstrated that in contrast to pediatric ALL, de novo AML is characterized by a very low burden of genomic alterations (Radtke, et al., PNAS, 2009). Samples for this study represented a cross-section of the different subtypes of pediatric AML. The only AML subtype that was an outlier from the above observations was acute megakaryocytic leukemia (AML FAB-M7), with the majority of these cases being characterized by complex chromosomal rearrangements and a high number of copy number alterations. To more fully define the genomic landscape of this subtype, we performed transcriptome sequence analysis on 14 pediatric FAB-M7 cases and mutation recurrence screening in a panel of 62 adult and pediatric AML FAB-M7 samples using the Illumina platform. Our results identified chromosomal rearrangements resulting in the expression of novel fusion transcripts in 11/14 cases. Remarkably, in 7/14 cases we detected an inversion on chromosome 16 that results in the juxtaposition of the CBFA2T3 gene next to the GLIS2 gene resulting in a CBFA2T3-GLIS2 chimeric gene that encoded an in frame fusion protein. This fusion led to the acquisition or preservation of self-renewal in colony forming assays, providing functional evidence for a role in leukemogenesis. In addition to novel chimeric transcripts, we found mutations in genes previously identified to play a role in megakaryoblastic leukemia that carry a proliferative advantage to the cell, such as JAK2 and MPL. These data demonstrate that AML FAB-M7 is characterized by cooperating Class I and Class II mutations leading to leukemogenesis.</p>

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Project description:St. Jude Children's Research Hospital - Washington University Pediatric Cancer Genome Project (PCGP): Somatic Mutations in Pediatric AML FAB-M7 Subtype by Whole Transcriptome Sequencing

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The landscape of somatic alterations in epigenetic genes across 21 pediatric cancers

Project description:As a part of the St Jude Children’s Research Hospital-Washington University Pediatric Cancer Genome Project (PCGP), we adapted deep sequencing technologies and have sequenced 1025 tumor samples from 21 diseases covering brain, solid tumors and leukemias. We analyzed the genomic DNA sequences, copy number variations and structural rearrangements of 633 genes whose proteins are involved in epigenetic machineries, including those that covalently modify DNA and histones, and structurally reorder chromatin. To examine gene expression level of mutated histone genes, we analyzed gene expression in a group of 40 non-ETP T-lineage ALL samples using Affymetrix GeneChip HT HG-U133+ PM arrays (including 37 samples deposited in GSE28703 and 3 additional arrays not studied previously). The results provide us the knowledge of potential therapeutic targets for pediatric cancer treatment and improvement of personalized therapy. Gene expression profiling was performed on 40 non ETP T-lineage acute lymphoblastic leukemia samples. No control or reference samples were included.

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St. Jude Children's Research Hospital - Washington University Pediatric Cancer Genome Project: Whole Genome Sequencing of Childhood Hypodiploid Acute Lymphoblastic Leukemia

Project description:St. Jude Children's Research Hospital - Washington University Pediatric Cancer Genome Project: Whole Genome Sequencing of Childhood Hypodiploid Acute Lymphoblastic Leukemia

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Project description:The goal of this study is to define the global gene expression profile of primary leukemic blasts from patients with different forms of myeloid leukemia and different FAB subtypes. Here we report the global gene expression profile of 2 patients with AML FAB M5, 2 patients with AML FAB M7, 3 patients with Down syndrome AML FAB M7 and 3 patients with Down syndrome transient leukemia.

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