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Status |
Public on Mar 01, 2024 |
Title |
BRG1/BRM inhibitor targets AML stem cells and exerts superior preclinical efficacy combined with BET or Menin inhibitor (ChIP-Seq) |
Organism |
Homo sapiens |
Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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Summary |
BRG1 (SMARCA4) and BRM (SMARCA2) are the mutually exclusive core ATPases of the chromatin remodeling BAF (BRG1/BRM-associated factor) complexes. They enable transcription factors/co-factors to access enhancers/promoter and modulate gene-expressions responsible for cell growth and differentiation of AML stem/progenitor cells. In AML with MLL1r (MLL1 rearrangement) or mutant (mt) NPM1, although Menin inhibitor (MI) treatment induces clinical remissions, most patients either fail to respond or relapse, some harboring Menin mutations. FHD-286 is an orally bioavailable, selective inhibitor of BRG1/BRM under clinical development in AML. Present studies show that FHD-286 induces differentiation and lethality in AML cells with MLL1r or mtNPM1, concomitantly causing perturbed chromatin accessibility and repression of c-Myc, PU.1 and CDK4/6. Co-treatment with FHD-286 and decitabine, BET inhibitor (BETi) or MI, or venetoclax synergistically induced in vitro lethality in AML cells with MLL1r or mtNPM1. In patient-derived xenograft (PDX) models of AML with MLL1r or mtNPM1, FHD-286 treatment reduced AML burden, improved survival, and attenuated AML-initiating potential of stem-progenitor cells. Compared to each drug, co-treatment with FHD-286 and BETi, MI, decitabine or venetoclax significantly reduced AML burden and improved survival, without inducing significant toxicity. These findings highlight the FHD-286-based combinations as promising therapy of AML with MLL1r or mtNPM1.
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Overall design |
Chromatin immunoprecipitation DNA-sequencing (ChIP-seq) for the histone modification H3K27Ac, BRG1 and BRM in AML MOLM13 cell line and patient-derived AML cells.
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Contributor(s) |
Fiskus W, Bhalla KN |
Citation missing |
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Submission date |
Jan 10, 2024 |
Last update date |
Mar 02, 2024 |
Contact name |
Xiaoping Su |
E-mail(s) |
xsu1@mdanderson.org
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Phone |
8328179083
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Organization name |
MD Anderson Cancer Center
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Street address |
7300 Brompton St, Apt 5633
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City |
Houston |
State/province |
Texas |
ZIP/Postal code |
77025 |
Country |
USA |
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Platforms (1) |
GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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Samples (12)
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GSM8010545 |
MOLM13, 100 nM FHD-286, BRG1 |
GSM8010546 |
MOLM13 Control, input |
GSM8010547 |
MOLM13, 100 nM FHD-286, input |
GSM8010548 |
DF16835, Control, BRM |
GSM8010549 |
DF16835, 100 nM FHD-286, BRM |
GSM8010550 |
DF16835, Control, H3K27Ac |
GSM8010551 |
DF16835, 100 nM FHD-286, H3K27Ac |
GSM8010552 |
DF16835, Control, input |
GSM8010553 |
DF16835, 100 nM FHD-286, input |
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This SubSeries is part of SuperSeries: |
GSE252938 |
BRG1/BRM inhibitor targets AML stem cells and exerts superior preclinical efficacy combined with BET or Menin inhibitor |
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Relations |
BioProject |
PRJNA1063278 |
Supplementary file |
Size |
Download |
File type/resource |
GSE252935_RAW.tar |
6.2 Mb |
(http)(custom) |
TAR (of BROADPEAK, NARROWPEAK) |
SRA Run Selector |
Raw data are available in SRA |
Processed data provided as supplementary file |
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