Journal
CELL STEM CELL
Volume 28, Issue 4, Pages 623-+Publisher
CELL PRESS
DOI: 10.1016/j.stem.2020.12.017
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Funding
- NIH [NCI 1R21CA194679, R01CA205944, NIDDK R01DK114468]
- NIH (UCSD Specialized Cancer Center Support Grant) [2P30CA023100-33]
- CIRM [TRAN110540]
- LLS Blood Cancer Discoveries
- NASA [NRA NNJ13ZBG001N]
- UC San Diego Health Sciences Academic Senate
- Altman Clinical and Translational Research Institute (UCSD NIH CTSA) [UL1TR001442]
- Ionis Pharmaceuticals
- Moores Family Foundation
- Strauss Family Foundation
- Koman Family Foundation
- Sanford Stem Cell Clinical Center
- UC San Diego Moores Cancer Center
- San Diego Multiple Myeloma Support Group
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In multiple myeloma, the inflammatory and anti-viral pathways play a role in disease progression and the generation of cancer stem cells. The inhibition of interferon regulatory factor 4 (IRF4) using antisense oligonucleotides (ASOs) shows promise in impairing myeloma cell survival and reducing tumor burden in pre-clinical models. Targeting IRF4 may offer a new strategy for preventing myeloma relapse driven by progenitor cells.
In multiple myeloma, inflammatory and anti-viral pathways promote disease progression and cancer stem cell generation. Using diverse pre-clinical models, we investigated the role of interferon regulatory factor 4 (IRF4) in myeloma progenitor regeneration. In a patient-derived xenograft model that recapitulates IRF4 pathway activation in human myeloma, we test the effects of IRF4 antisense oligonucleotides (ASOs) and identify a lead agent for clinical development (ION251). IRF4 overexpression expands myeloma progenitors, while IRF4 ASOs impair myeloma cell survival and reduce IRF4 and c-MYC expression. IRF4 ASO monotherapy impedes tumor formation and myeloma dissemination in xenograft models, improving animal survival. Moreover, IRF4 ASOs eradicate myeloma progenitors and malignant plasma cells while sparing normal human hematopoietic stem cell development. Mechanistically, IRF4 inhibition disrupts cell cycle progression, downregulates stem cell and cell adhesion transcript expression, and promotes sensitivity to myeloma drugs. These findings will enable rapid clinical development of selective IRF4 inhibitors to prevent myeloma progenitor-driven relapse.
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