|
| Status |
Public on Jul 31, 2018 |
| Title |
Targeting the MTF2-MDM2 Axis Sensitizes Refractory Acute Myeloid Leukemia to Chemotherapy [RNA-Seq] |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
Deep sequencing has revealed that epigenetic modifiers are the most mutated genes in acute myeloid leukemia (AML). Thus, elucidating epigenetic dysregulation in AML is crucial to understand disease mechanisms. Here, we demonstrate that Metal Response Element Binding Transcription Factor 2/Polycomblike 2 (MTF2/PCL2) plays a fundamental role in the Polycomb repressive complex 2 (PRC2) and that its loss elicits an altered epigenetic state underlying refractory AML. Unbiased systems analyses identified the loss of MTF2-PRC2 repression of MDM2 as central to, and therefore a biomarker for, refractory AML. Thus, immature MTF2- deficient CD34+CD38- cells overexpress MDM2, thereby inhibiting p53 that leads to chemoresistance due to defects in cell cycle regulation and apoptosis. Targeting this dysregulated signaling pathway by MTF2 overexpression or MDM2 inhibitors sensitized refractory patient leukemic cells to induction chemotherapeutics and prevented relapse in AML patient-derived xenograft (PDX) mice. Therefore, we have uncovered a direct epigenetic mechanism by which MTF2 functions as a tumor suppressor required for AML chemotherapeutic sensitivity and identified a potential therapeutic strategy to treat refractory AML.
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| |
|
| Overall design |
Fold change analysis between treatment and control
|
| |
|
| Contributor(s) |
Maganti HB, Stanford WL |
| Citation(s) |
30115703 |
| |
| Submission date |
Apr 28, 2017 |
| Last update date |
May 15, 2019 |
| Contact name |
William Stanford |
| E-mail(s) |
wstanford@ohri.ca
|
| Phone |
613-737-8899
|
| Organization name |
Ottawa Hospital Research Institute
|
| Lab |
Stanford
|
| Street address |
501 Smyth Road
|
| City |
Ottawa |
| State/province |
Ontario |
| ZIP/Postal code |
K1H 8L6 |
| Country |
Canada |
| |
|
| Platforms (1) |
| GPL11154 |
Illumina HiSeq 2000 (Homo sapiens) |
|
| Samples (6)
|
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| This SubSeries is part of SuperSeries: |
| GSE98380 |
Targeting the MTF2-MDM2 Axis Sensitizes Refractory Acute Myeloid Leukemia to Chemotherapy |
|
| Relations |
| BioProject |
PRJNA384957 |
| SRA |
SRP105765 |
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