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| Status |
Public on Sep 24, 2020 |
| Title |
Aging of preleukemic thymocytes drives CpG island hypermethylation in T-cell acute lymphoblastic leukemia [RNAseq_DACPDX] |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
Cancer cells display DNA hypermethylation at specific CpG islands in comparison to their normal healthy counterparts, but the mechanism that drives this so-called CpG island methylator phenotype (CIMP) remains poorly understood. Here, we show that CpG island methylation in human T-cell acute lymphoblastic leukemia (T-ALL) mainly occurs at promoters of PRC2 target genes that are not expressed in normal or malignant T-cells and which display a reciprocal association with H3K27me3 binding. In addition, we found that this aberrant methylation profile shows a strong correlation with the epigenetic age of the leukemic T cells and elucidate that a similar CpG island methylation signature is gradually established in aging pre-leukemic thymocytes from CD2-Lmo2 transgenic mice. Finally, we unexpectedly uncover that this age-related CpG island hypermethylation signature is completely resistant to the FDA-approved hypomethylating agent Decitabine. Altogether, our work demonstrates that DNA methylation reflects the epigenetic history of leukemic T cells and suggests that methylation-based subtypes of human T-ALL have followed a different trajectory towards T-cell transformation, possibly mediated by differences in the self-renewing capacity of the putative T-ALL cell-of-origin. Given that the concept of preleukemic thymocytes has only been reported in T-ALL mouse models so far, we here provide, for the first time, conceptual evidence that a pre-leukemic phase might also be involved in the pathogenesis of the human disease.
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| Overall design |
RNAseq of T-ALL patient derived xenografts treated with Decitabine or vehicle control
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| |
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| Contributor(s) |
Roels J, Thénoz M, Van Vlierberghe P |
| Citation missing |
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| |
| Submission date |
Jul 29, 2020 |
| Last update date |
Sep 24, 2020 |
| Contact name |
Juliette Roels |
| E-mail(s) |
roels.juliette@gene.com
|
| Phone |
6505807476
|
| Organization name |
Genentech
|
| Street address |
1 DNA Way
|
| City |
South San Francisco |
| State/province |
CA |
| ZIP/Postal code |
94080 |
| Country |
USA |
| |
|
| Platforms (1) |
| GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
|
| Samples (12)
|
| GSM4699411 |
Spleen-PDX T-ALL1 Decitabine Rep1 RNA-seq |
| GSM4699412 |
Spleen-PDX T-ALL1 Decitabine Rep2 RNA-seq |
| GSM4699413 |
Spleen-PDX T-ALL1 Decitabine Rep3 RNA-seq |
| GSM4699414 |
Spleen-PDX T-ALL2 DMSO Rep1 RNA-seq |
| GSM4699415 |
Spleen-PDX T-ALL2 DMSO Rep2 RNA-seq |
| GSM4699416 |
Spleen-PDX T-ALL2 DMSO Rep3 RNA-seq |
| GSM4699417 |
Spleen-PDX T-ALL2 Decitabine Rep1 RNA-seq |
| GSM4699418 |
Spleen-PDX T-ALL2 Decitabine Rep2 RNA-seq |
| GSM4699419 |
Spleen-PDX T-ALL2 Decitabine Rep3 RNA-seq |
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| This SubSeries is part of SuperSeries: |
| GSE155339 |
Aging of preleukemic thymocytes drives CpG island hypermethylation in T-cell acute lymphoblastic leukemia |
|
| Relations |
| BioProject |
PRJNA649431 |
| SRA |
SRP274093 |
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