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Series GSE252935 Query DataSets for GSE252935
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
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.
 
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.
 
Contributor(s) Fiskus W, Bhalla KN
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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
Phone 8328179083
Organization name MD Anderson Cancer Center
Street address 7300 Brompton St, Apt 5633
City Houston
State/province Texas
ZIP/Postal code 77025
Country USA
 
Platforms (1)
GPL24676 Illumina NovaSeq 6000 (Homo sapiens)
Samples (12)
GSM8010542 MOLM13, Control, H3K27Ac
GSM8010543 MOLM13, 100 nM FHD-286, H3K27Ac
GSM8010544 MOLM13, Control, BRG1
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
Relations
BioProject PRJNA1063278

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE252935_RAW.tar 6.2 Mb (http)(custom) TAR (of BROADPEAK, NARROWPEAK)
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file

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