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Selective antisense oligonucleotide inhibition of human IRF4 prevents malignant myeloma regeneration via cell cycle

Phoebe K Mondala1, Ashni A Vora1, Tianyuan Zhou2

  • 1Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.

Cell Stem Cell
|January 21, 2021
PubMed

Insights

Interferon regulatory factor 4 (IRF4) drives multiple myeloma progression. IRF4 antisense oligonucleotides (ASOs) effectively target and eliminate myeloma stem cells, offering a promising new therapeutic strategy for preventing disease relapse.

Area of Science:

  • Oncology
  • Hematology
  • Molecular Biology

Background:

  • Inflammatory and anti-viral pathways contribute to multiple myeloma progression and the generation of cancer stem cells.
  • Interferon regulatory factor 4 (IRF4) plays a critical role in the regeneration of myeloma progenitor cells.

Purpose of the Study:

  • To investigate the role of IRF4 in myeloma progenitor regeneration using preclinical models.
  • To evaluate the therapeutic potential of IRF4 antisense oligonucleotides (ASOs) in multiple myeloma.

Main Methods:

  • Utilized patient-derived xenograft models of multiple myeloma.
  • Tested the efficacy of IRF4 antisense oligonucleotides (ASOs), including a lead agent (ION251).
  • Assessed the impact of IRF4 inhibition on myeloma cell survival, progenitor regeneration, and tumor dissemination.

Main Results:

  • IRF4 overexpression was found to expand myeloma progenitors.
  • IRF4 ASOs significantly impaired myeloma cell survival and reduced IRF4 and c-MYC expression.
  • IRF4 ASO monotherapy impeded tumor formation, reduced dissemination in xenograft models, and improved animal survival.
  • IRF4 ASOs eradicated myeloma progenitors and malignant plasma cells while preserving normal hematopoietic stem cell development.

Conclusions:

  • IRF4 inhibition disrupts cell cycle progression, downregulates stem cell and cell adhesion gene expression, and enhances sensitivity to existing myeloma drugs.
  • Selective IRF4 inhibitors demonstrate potential for preventing myeloma progenitor-driven relapse and warrant rapid clinical development.
Keywords:
CXCR4IRF4MYCantisense oligonucleotidebone marrowcancer stem cellscell cycleinterferon regulatory factor 4multiple myelomatranslational research

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