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| Status |
Public on Nov 14, 2016 |
| Title |
DNMT3A R882 mutations promote anthacyline resistance through impaired DNA-damage sensing [Bisulfite-Seq] |
| Organism |
Mus musculus |
| Experiment type |
Methylation profiling by high throughput sequencing
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| Summary |
Although the majority of acute myeloid leukemia (AML) patients initially respond to chemotherapy, most of them subsequently relapse due to persistent, chemoresistant disease. However, the mechanistic basis by which AML cells persist during chemotherapy has not been fully delineated. Recurrent somatic mutations in the DNA methyltransferase 3A gene (DNMT3A), most frequently at arginine 882 (DNMT3Amut), are commonly observed in AML patients, and are also detected in elderly subjects with clonal hematopoiesis in the absence of leukemic transformation. DNMT3Amut AML patients have an inferior outcome when treated with standard dose daunorubicin-based induction chemotherapy, suggesting that DNMT3Amut AML cells can persist following chemotherapy and drive relapse. DNMT3Amut cells show impaired nucleosome eviction and chromatin remodeling in response to DNA damage in the setting of anthracycline exposure. This defect leads to an inability to sense and repair DNA damage, which results in the accumulation of single-stranded DNA breaks and increased mutagenesis. Our studies identify a critical role for DNMT3A R882 mutations in driving AML chemoresistance, and highlight the importance of chromatin remodeling in the response to cytotoxic chemotherapy.
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| Overall design |
We have generated a novel genetic mouse model conditionally expressing mutant Dnmt3a from an endogenous locus and examined transcriptomes from FACS-sorted LSK populations from Dnmt3a+/+ (wt_Mx+), Dnmt3a+/m (cKI_Mx+), and Dnmt3a+/- (cKI_Cre-) animals at 6 months of age
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| Contributor(s) |
Guryanova OA, Spitzer B, Garrett-Bakelman FE, Sheridan C, Neelamraju Y, Levine RL |
| Citation(s) |
27841873 |
| |
| Submission date |
Sep 12, 2016 |
| Last update date |
May 15, 2019 |
| Contact name |
Barbara Spitzer |
| E-mail(s) |
spitzerb@mskcc.org
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| Organization name |
Memorial Sloan Kettering Cancer Center
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| Lab |
Levine Lab
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| Street address |
411 E 67th St
|
| City |
New York |
| State/province |
NY |
| ZIP/Postal code |
10065 |
| Country |
USA |
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| Platforms (1) |
| GPL17021 |
Illumina HiSeq 2500 (Mus musculus) |
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| Samples (9)
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| This SubSeries is part of SuperSeries: |
| GSE72883 |
DNMT3A R882 mutations promote anthacyline resistance through impaired DNA-damage sensing |
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| Relations |
| BioProject |
PRJNA342651 |
| SRA |
SRP089720 |
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