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Status |
Public on Apr 09, 2022 |
Title |
Effective therapy of AML with RUNX1 mutation by co-treatment with inhibitors of protein translation and BCL2 [ChIP-seq] |
Organism |
Homo sapiens |
Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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Summary |
Majority of RUNX1 mutations in AML are missense or deletion-truncation and behave as loss-of-function mutations. Following standard therapy, AML patients expressing mtRUNX1 exhibit inferior clinical outcome than those without mutant RUNX1. Studies presented here demonstrate that as compared to AML cells lacking mtRUNX1, their isogenic counterparts harboring mtRUNX1 display impaired ribosomal biogenesis and differentiation, as well as exhibit reduced levels of wild-type RUNX1, PU.1 and c-Myc. Compared to AML cells with only wild-type RUNX1, AML cells expressing mtRUNX1 were also more sensitive to the protein translation inhibitor homoharringtonine (omacetaxine) and BCL2 inhibitor venetoclax. HHT treatment repressed enhancers and their BRD4 occupancy, as well as reduced levels of c-Myc, c-Myb, MCL1 and Bcl-xL. Consistent with this, co-treatment with omacetaxine and venetoclax or BET inhibitor induced synergistic in vitro lethality in AML expressing mtRUNX1. Compared to each agent alone, co-treatment with omacetaxine and venetoclax or BET inhibitor also displayed improved in vivo anti-AML efficacy, associated with improved survival of immune depleted mice engrafted with AML cells harboring mtRUNX1. These findings highlight superior efficacy of omacetaxine-based combination therapies for AML harboring mtRUNX1.
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Overall design |
8 samples
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Contributor(s) |
Mill CP, Bhalla KN |
Citation missing |
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Submission date |
Aug 12, 2021 |
Last update date |
Apr 10, 2022 |
Contact name |
Yuan Qi |
E-mail(s) |
yqi1@mdanderson.org
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Organization name |
University of Texas M.D. Anderson Cancer Center
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Department |
Bioinformatics & Computational Biology
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Street address |
1400 Pressler St
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City |
Houston |
State/province |
TX |
ZIP/Postal code |
77030-4008 |
Country |
USA |
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Platforms (1) |
GPL20301 |
Illumina HiSeq 4000 (Homo sapiens) |
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Samples (8)
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GSM5516049 |
OCIAML2 Runx1R174*/wt Control ChIP-Input |
GSM5516050 |
OCIAML2 Runx1R174*/wt 100nM HHT ChIP-Input |
GSM5516051 |
OCIAML2 Runx1R174*/wt Control ChIP-H3K27Ac |
GSM5516052 |
OCIAML2 Runx1R174*/wt 100nM HHT ChIP-H3K27Ac |
GSM5516053 |
OCIAML2 Runx1R174*/wt Control ChIP-Brd4 |
GSM5516054 |
OCIAML2 Runx1R174*/wt 100nM HHT ChIP-Brd4 |
GSM5516055 |
OCIAML2 Runx1R174*/wt Control ChIP-P300 |
GSM5516056 |
OCIAML2 Runx1R174*/wt 100nM HHT ChIP-P300 |
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This SubSeries is part of SuperSeries: |
GSE182023 |
Effective therapy of AML with RUNX1 mutation by co-treatment with inhibitors of protein translation and BCL2 |
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Relations |
BioProject |
PRJNA754174 |
SRA |
SRP332304 |