2. Academic Validation
  3. IRF4 requires ARID1A to establish plasma cell identity in multiple myeloma

IRF4 requires ARID1A to establish plasma cell identity in multiple myeloma

  • Cancer Cell. 2024 Jul 8;42(7):1185-1201.e14. doi: 10.1016/j.ccell.2024.05.026.
Arnold Bolomsky 1,  Michele Ceribelli 2,  Sebastian Scheich 1,  Kristina Rinaldi 1,  Da Wei Huang 1,  Papiya Chakraborty 1,  Lisette Pham 1,  George W Wright 3,  Tony Hsiao 1,  Vivian Morris 1,  Jaewoo Choi 1,  James D Phelan 1,  Ronald J Holewinski 4,  Thorkell Andresson 4,  Jan Wisniewski 5,  Deanna Riley 6,  Stefania Pittaluga 6,  Elizabeth Hill 1,  Craig J Thomas 7,  Jagan Muppidi 1,  Ryan M Young 8
Affiliations

Affiliations

  • 1 Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  • 2 Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20892, USA.
  • 3 Biometric Research Branch, DCTD, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  • 4 Protein Mass Spectrometry Group, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21701, USA.
  • 5 Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  • 6 Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  • 7 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.
  • 8 Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: youngrm@nih.gov.
PMID: 38906156 DOI: 10.1016/j.ccell.2024.05.026
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.

Keywords

ARID1A; CRISPR; IRF4; MYC; SWI/SNF; multiple myeloma; plasma cell; proteogenomics; proteomics; transcription.

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