Dimethyl fumarate restores apoptosis sensitivity and inhibits tumor growth and metastasis in CTCL by targeting NF-κB

Jan P. Nicolay, Karin Müller-Decker, Anne Schroeder, Markus Brechmann, Markus Möbs, Cyrill Géraud, Chalid Assaf, Sergij Goerdt, Peter H. Krammer and Karsten Gülow

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  • RE: Dimethyl fumarate also inhibits CLL B-cell survival
    • Christina C.N Wu, Scientist UC San Diego Moores Cancer Center
    • Other Contributors:
      • Fitzgerald S Lao, Scientist
      • Hongying Li, Biostatistician
      • Karen Messer, Biostatistician
      • Dennis A Carson, Scientist
      • Michael Y Choi, Hematologist

    Nicolay et al astutely showed that the immunomodulating drug, dimethylfumarate (DMF), could be repurposed as a treatment for patients with cutaneous T-cell lymphoma (CTCL), with selective inhibition of the NF-κB pathway, tumor cell survival, and tumor growth with both in vitro and in vivo disease models.1

    Corroborating these findings, we have observed similar effects in B-cell chronic lymphocytic leukemia (CLL). DMF and other α-β unsaturated carbonyls modulate Nrf2, with cytotoxicity in CLL cells at similar concentrations as reported for CTCL cells.2

    We have subsequently determined that DMF effectively induces clearance of CLL cells in a murine CLL xenograft model (Figure A). We implanted primary leukemic cells from patients with CLL into the peritoneum of immune-deficient mice that were then treated for one week with DMF at pharmacologically relevant doses (3-30 mg/kg by oral gavage BID). DMF inhibited the survival of CLL cells in this model (Figure B).3

    The known mechanisms of action by which DMF inhibits NF-κB include direct targeting of p50 and p65 as well as indirect effects. Interestingly, we have also found that DMF has many other effects, including inhibition of canonical Wnt signaling, as confirmed by a cell-based reporter gene assay in which DMF inhibited LEF/TCF dependent gene expression at low μM levels. We have also observed that DMF inhibited constitutive STAT1 phosphorylation (Figure C) and downstream IRF8 expression in CLL cells, which...

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    Conflict of Interest:
    None declared.