|
| Status |
Public on Nov 16, 2022 |
| Title |
A molecular switch between mammalian MLL complexes dictates response to Menin-MLL inhibition [ChIP-seq] |
| Organism |
Mus musculus |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
|
| Summary |
The chromatin adaptor Menin interacts with oncogenic fusion proteins encoded by MLL1-rearrangements (MLL1-r), and small molecules that disrupt these associations are currently in clinical trials for the treatment of leukemia. Here, we delineate a molecular switch between the MLL1-Menin and MLL3/4-UTX chromatin modifying complexes that dictates response to Menin-MLL inhibitors. We show that Menin safeguards leukemia cell fitness by impeding binding of the histone demethylase UTX at a subset of non-canonical target gene promoters. Disrupting the interaction between Menin and MLL1 leads to UTX-dependent transcriptional activation of genes with tumor suppressive function. We show that this epigenetic mechanism is operative in murine and human models of AML, and clinical responses to Menin-MLL inhibition in primary human leukemia are accompanied by induction of tumor suppressive gene expression at Menin-UTX targets. These findings shed light on the context-dependent and often antagonistic roles that chromatin regulators exhibit in development and disease and provide mechanistic insight for rational design of targeted epigenetic therapies.
|
| |
|
| Overall design |
ChIP-Seq for Menin, UTX, MLL1, MLL3/4 and various histone post-translational modifications in mouse and human leukemia cells and fibroblasts.
|
| |
|
| Contributor(s) |
Soto-Feliciano YM, Sánchez-Rivera FJ, Perner F, Armstrong SA, Lowe SW, Allis CD |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
| |
| Submission date |
Oct 27, 2021 |
| Last update date |
Nov 19, 2022 |
| Contact name |
Douglas Barrows |
| E-mail(s) |
dbarrows@rockefeller.edu
|
| Phone |
7749940981
|
| Organization name |
Rockefeller University
|
| Street address |
1230 York Ave
|
| City |
New York |
| State/province |
NY |
| ZIP/Postal code |
10065 |
| Country |
USA |
| |
|
| Platforms (1) |
| GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
|
| Samples (30)
|
|
| This SubSeries is part of SuperSeries: |
| GSE186711 |
A molecular switch between mammalian MLL complexes dictates response to Menin-MLL inhibition |
|
| Relations |
| BioProject |
PRJNA775615 |
| SRA |
SRP343461 |
Less...
More...