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IRF4 requires ARID1A to establish plasma cell identity in multiple myeloma

  1. Author:
    Bolomsky, Arnold
    Ceribelli, Michele
    Scheich, Sebastian
    Rinaldi, Kristina
    Huang, Da Wei
    Chakraborty, Papiya
    Pham, Lisette
    Wright, George W
    Hsiao, Tony
    Morris, Vivian
    Choi, Jaewoo
    Phelan, James D
    Holewinski,Ronald
    Andresson,Thorkell
    Wisniewski, Jan
    Riley, Deanna
    Pittaluga, Stefania
    Hill, Elizabeth
    Thomas, Craig J
    Muppidi, Jagan
    Young, Ryan M

  2. Author Address

    Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA., Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20892, USA., Biometric Research Branch, DCTD, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA., Protein Mass Spectrometry Group, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21701, USA., Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA., Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA., Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20892, USA., Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: youngrm@nih.gov.,
    1. Year: 2024
    2. Date: Jul 8
    3. Epub Date: 2024 06 14
  2. Journal: Cancer Cell
    1. 42
    2. 7
    3. Pages: 1185-1201
  4. Type of Article: Article
  1. Abstract:

    Multiple myeloma (MM) is an incurable plasma cell malignancy that exploits transcriptional networks driven by IRF4. We employ a multi-omics approach to discover IRF4 vulnerabilities, integrating functional genomics screening, spatial proteomics, and global chromatin mapping. ARID1A, a member of the SWI/SNF chromatin remodeling complex, is required for IRF4 expression and functionally associates with IRF4 protein on chromatin. Deleting Arid1a in activated murine B cells disrupts IRF4-dependent transcriptional networks and blocks plasma cell differentiation. Targeting SWI/SNF activity leads to rapid loss of IRF4-target gene expression and quenches global amplification of oncogenic gene expression by MYC, resulting in profound toxicity to MM cells. Notably, MM patients with aggressive disease bear the signature of SWI/SNF activity, and SMARCA2/4 inhibitors remain effective in immunomodulatory drug (IMiD)-resistant MM cells. Moreover, combinations of SWI/SNF and MEK inhibitors demonstrate synergistic toxicity to MM cells, providing a promising strategy for relapsed/refractory disease. Published by Elsevier Inc.

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External Sources

  1. View Full Text
  2. DOI: 10.1016/j.ccell.2024.05.026
  3. PMID: 38906156
  4. PMCID: PMC11233249
  5. View record in Web of Science®
  6. WOS: 001267675200001
  7. PII : S1535-6108(24)00217-4

Library Notes

  1. Fiscal Year: FY2023-2024
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