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Series GSE253711 Query DataSets for GSE253711
Status Public on May 01, 2024
Title IRF4 requires ARID1A to establish plasma cell identity in multiple myeloma (CUT&RUN human 8).
Organism Homo sapiens
Experiment type Genome binding/occupancy profiling by high throughput sequencing
Summary Multiple myeloma (MM) is an incurable malignancy of plasma cells that exploits transcriptional networks underpinning normal plasma cell biology to drive malignant growth and survival. The transcription factor IRF4 serves as the principal architect of plasma cell identity, and MM cells are addicted to IRF4 expression for their survival. To discover unique molecular vulnerabilities in MM, we employ a multi-omics approach integrating functional genomics screening, spatial-proteomics, and global chromatin mapping. We find that ARID1A, a member of the SWI/SNF chromatin remodeling complex, is both required for IRF4 expression and functionally associated with IRF4 protein on chromatin. Conditional deletion of Arid1a in activated murine B cells thwarts subsequent plasma cell differentiation by disrupting IRF4-dependent transcriptional networks, thus defining ARID1A as a novel plasma cell vulnerability. Targeting ARID1A-dependent SWI/SNF activity via SMARCA2/4 inhibition induces a rapid loss of IRF4-target gene expression and quenches global oncogenic amplification of gene expression driven by MYC, resulting in profound toxicity to MM cells. Notably, SWI/SNF-dependent genes are upregulated in MM patients with aggressive disease, and SMARCA2/4 inhibitors retain their activity in immunomodulatory drug (IMiD)-resistant MM cells. To fully harness the potential of these drugs, we use combinatorial drug screens to uncover profound synergistic toxicity between SMARCA2/4 and MEK inhibitors. Thus, targeting SWI/SNF activity potently represses an IRF4-MYC feed forward loop and provides a feasible path forward to effectively treat this incurable disease.
 
Overall design Cut&Run analysis to determine IRF4 and ARID1A chromatin binding profiles in SKMM1 multiple myeloma cells treated with control (DMSO) versus 1000 nM AU15330 for 3 hours.
 
Contributor(s) Bolomsky A, Young RM
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Submission date Jan 19, 2024
Last update date May 01, 2024
Contact name David Huang
Organization name National Cancer Institute
Street address 9000 Rockville Pike
City Bethesda
State/province Maryland
ZIP/Postal code 20892-0001
Country USA
 
Platforms (1)
GPL30173 NextSeq 2000 (Homo sapiens)
Samples (8)
GSM8026856 SKMM1 (CUT&RUN2) ARID1A DMSO 1
GSM8026857 SKMM1 (CUT&RUN2) ARID1A DMSO 2
GSM8026858 SKMM1 (CUT&RUN2) ARID1A AU15330 1
This SubSeries is part of SuperSeries:
GSE253716 IRF4 requires ARID1A to establish plasma cell identity in multiple myeloma
Relations
BioProject PRJNA1066813

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
GSE253711_SKMM1_ARID1A_IRF4_cutRun_Peaks.zip 15.7 Mb (ftp)(http) ZIP
SRA Run SelectorHelp
Raw data are available in SRA
Processed data are available on Series record

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