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| Status |
Public on Mar 15, 2017 |
| Title |
Activation of the LMO2 oncogene through a somatically acquired neomorphic promoter in T-Cell Acute Lymphoblastic Leukemia |
| Organism |
Homo sapiens |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
Somatic mutations within non-coding genomic regions that aberrantly activate oncogenes have remained poorly characterized. Here we describe recurrent activating intronic mutations of LMO2, a prominent oncogene in T-cell acute lymphoblastic leukaemia (T-ALL). Heterozygous mutations were identified in PF-382 and DU.528 T-ALL cell lines, in addition to 3.7% (6/160) of paediatric and 5.5% (9/163) of adult T-ALL patient samples. The majority of indels harbor de novo MYB, ETS1 or RUNX1 consensus binding sites. Analysis of 5’-capped RNA transcripts in mutant cell lines identified the usage of an intermediate promoter site, with consequential monoallelic LMO2 overexpression. CRISPR/Cas9-mediated disruption of the mutant allele in PF-382 cells markedly downregulated LMO2 expression, establishing clear causality between the mutation and oncogene dysregulation. Furthermore, the spectrum of CRISPR/Cas9-derived mutations provide important insights into the interconnected contributions of functional transcription factor binding. Finally, these mutations occur in the same intron as retroviral integration sites in gene therapy induced T-ALL, suggesting that such events occur at preferential sites in the non-coding genome.
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| Overall design |
ChIP-Seq for MYB in T cell leukemia (T-ALL) cell lines
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| Contributor(s) |
Rahman S, Magnussen M, León TE, Farah N, Li Z, Abraham BJ, Alapi KZ, Mitchell RJ, Naughton T, Fielding AK, Pizzey A, Bustraan S, Allen C, Popa T, Pike-Overzet K, Garcia-Perez L, Gale RE, Linch DC, Staal FJ, Young RA, Look AT, Mansour MR |
| Citation(s) |
28270453 |
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| Submission date |
Jan 24, 2017 |
| Last update date |
May 15, 2019 |
| Contact name |
Richard A Young |
| E-mail(s) |
young_computation@wi.mit.edu
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| Phone |
617-258-5219
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| Organization name |
Whitehead Institute for Biomedical Research
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| Lab |
Young Lab
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| Street address |
9 Cambridge Center
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| City |
Cambridge |
| State/province |
MA |
| ZIP/Postal code |
02142 |
| Country |
USA |
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| Platforms (1) |
| GPL16791 |
Illumina HiSeq 2500 (Homo sapiens) |
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| Samples (5)
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| GSM2466686 |
ChIP:MYB_ab45150_LOUCY_052615 [lab: Look-DFCI] |
| GSM2466687 |
ChIP: MYB_ab45150_PF-382_032615 [lab: Look-DFCI] |
| GSM2466688 |
ChIP: MYB_ab45150_DU.528_032615 [lab: Look-DFCI] |
| GSM2466689 |
ChIP:JURKAT_Input_052616 [lab: Look-DFCI] |
| GSM2466690 |
ChIP:LOUCY_Input_052615 [lab: Look-DFCI] |
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| Relations |
| BioProject |
PRJNA363039 |
| SRA |
SRP097676 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE94000_RAW.tar |
351.5 Mb |
(http)(custom) |
TAR (of WIG) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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