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| Status |
Public on Nov 27, 2012 |
| Title |
Integrative Epigenomic Analysis Identifies Biomarkers and Therapeutic Targets in Adult B-Acute Lymphoblastic Leukemia [methylation profiling] |
| Organism |
Homo sapiens |
| Experiment type |
Methylation profiling by genome tiling array
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| Summary |
We performed DNA methylation (HELP array) and gene expression profiling in 215 samples of adult B-lineage acute lymphoblastic leukemia (ALL) and 12 normal preB samples. Adult B-lineage acute lymphoblastic leukemia (B-ALL) is an aggressive disease with <40% long-term survival. Genetic alterations such as BCR/ABL, E2A/PBX1 and MLL rearrangement (tMLL) define distinct B-ALL subtypes, which are associated with poor clinical outcome. It has been shown that these B-ALL subtypes have distinct expression profiles. However, the role of the epigenome in shaping these expression profiles and how the aberrant epigenetic gene regulation contributes to the biological and clinical features of those ALL subtypes is largely unknown. To address this question, we performed genome-wide DNA methylation and gene expression profiling on a large cohort of 215 well-characterized adult B-ALL specimens from the ECOG E2993 phase III clinical trial and a cohort of normal precursor B (preB) cells from 12 healthy bone marrows. The integrative analysis of these profiles led to the identification of key gene networks deregulated at the epigenetic and transcriptional levels within each subtype. In BCR/ABL, we identified a network centered on IL2RA(CD25), which is itself hypomethylated and overexpressed in most BCR/ABL B-ALL and confers poor clinical outcomes. In the tMLL subtype, we uncovered aberrant epigenetic and transcriptional activities that include hypomethylation and upregulation of FLT3 and BCL6. After showing that MLL/AF4 fusion protein binds to these genes as well as other hypomethylated and overexpressed genes in tMLL ALL cells, we showed that a specific BCL6 inhibitor, RI-BPI, kills tumor cells in both tMLL ALL cell lines and patient samples. BCL6 inhibition may therefore represent a novel therapeutic strategy for B-ALL patients with MLL translocations.
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| Overall design |
DNA methylation profiling in 215 samples of adult B-lineage acute lymphoblastic leukemia (ALL) and 12 normal preB samples, using DNA promoter methylation array (HELP array).
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| Contributor(s) |
Geng H, Elemento O, Melnick A |
| Citation(s) |
23107779, 23852341 |
| Submission date |
Jan 09, 2012 |
| Last update date |
Sep 15, 2014 |
| Contact name |
Huimin Geng |
| E-mail(s) |
huimin.geng@ucsf.edu
|
| Organization name |
UCSF
|
| Department |
Department of Laboratory Medicine
|
| Street address |
513 Parnassus Ave., MSB S-1480
|
| City |
San Francisco |
| State/province |
CA |
| ZIP/Postal code |
94143 |
| Country |
USA |
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| Platforms (1) |
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| Samples (227)
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| This SubSeries is part of SuperSeries: |
| GSE34941 |
Integrative Epigenomic Analysis Identifies Biomarkers and Therapeutic Targets in Adult B-Acute Lymphoblastic Leukemia |
|
| Relations |
| BioProject |
PRJNA156141 |
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