|
| Status |
Public on Nov 14, 2016 |
| Title |
Pluripotent Reprogramming of Human AML Resets Leukemic Behavior and Models Therapeutic Targeting of Subclones [methylation] |
| Organism |
Homo sapiens |
| Experiment type |
Methylation profiling by array
|
| Summary |
Understanding the contribution of abnormal genetic and epigenetic programs to acute myeloid leukemia (AML) is necessary for the integrated design of targeted therapies. To investigate this, we determined the effect of epigenetic reprogramming on leukemic behavior by generating induced pluripotent stem cells (iPSCs) from AML patient samples harboring MLL rearrangements. AML-derived iPSCs (AML-iPSCs) retained leukemic mutations, but reset leukemic DNA methylation/gene expression patterns and lacked leukemic potential. However, when differentiated into hematopoietic cells, AML-iPSCs reacquired the ability to give rise to leukemia in vivo and reestablished leukemic methylation/gene expression patterns, including an aberrant MLL signature, indicating that epigenetic reprogramming was insufficient to eliminate leukemic behavior. In one case, we identified distinct AML-iPSC KRAS mutant and wildtype subclones that demonstrated differential growth properties and therapeutic susceptibilities, predicting KRAS wildtype clonal relapse due to increased cytarabine resistance. Increased cytarabine resistance was further observed in a cohort of KRAS wildtype MLL-rearranged AML samples, demonstrating the utility of AML-iPSCs in predicting subclonal relapse and facilitating clonal targeting in AML.
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| |
|
| Overall design |
DNA methylation array profiling of normal and leukemic differentiated and iPSC populations
|
| |
|
| Contributor(s) |
Gentles A, Chao M |
| Citation(s) |
28089908 |
| |
| Submission date |
Nov 10, 2016 |
| Last update date |
Jul 25, 2021 |
| Contact name |
Andrew Gentles |
| Organization name |
Stanford University
|
| Street address |
1201 Welch Road
|
| City |
Stanford |
| State/province |
CA |
| ZIP/Postal code |
94305 |
| Country |
USA |
| |
|
| Platforms (1) |
| GPL13534 |
Illumina HumanMethylation450 BeadChip (HumanMethylation450_15017482) |
|
| Samples (48)
|
|
| This SubSeries is part of SuperSeries: |
| GSE89778 |
Pluripotent Reprogramming of Human AML Resets Leukemic Behavior and Models Therapeutic Targeting of Subclones |
|
| Relations |
| BioProject |
PRJNA353556 |
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