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Lenalidomide downregulates the cell survival factor, interferon regulatory factor‐4, providing a potential mechanistic link for predicting response
Author(s) -
LopezGirona Antonia,
Heintel Daniel,
Zhang LingHua,
Mendy Derek,
Gaidarova Svetlana,
Brady Helen,
Bartlett Justin Blake,
Schafer Peter H.,
Schreder Martin,
Bolomsky Arnold,
Hilgarth Bernadette,
Zojer Niklas,
Gisslinger Heinz,
Ludwig Heinz,
Daniel Tom,
Jäger Ulrich,
Chopra Rajesh
Publication year - 2011
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/j.1365-2141.2011.08689.x
Subject(s) - lenalidomide , irf4 , multiple myeloma , cancer research , medicine , oncology , immunology , biology , transcription factor , biochemistry , gene
Summary Overexpression of the transcription factor interferon regulatory factor‐4 (IRF4), which is common in multiple myeloma (MM), is associated with poor prognosis. Patients with higher IRF4 expression have significantly poorer overall survival than those with low IRF4 expression. Lenalidomide is an IMiD ® immunomodulatory compound that has both tumouricidal and immunomodulatory activity in MM. This study showed that lenalidomide downregulated IRF4 levels in MM cell lines and bone marrow samples within 8 h of drug exposure. This was associated with a decrease in MYC levels, as well as an initial G1 cell cycle arrest, decreased cell proliferation, and cell death by day 5 of treatment. In eight MM cell lines, high IRF4 levels correlated with increased lenalidomide sensitivity. The clinical significance of this observation was investigated in 154 patients with MM. Among MM patients with high levels of IRF4 expression, treatment with lenalidomide led to a significantly longer overall survival than other therapies in a retrospective analysis. These data confirm the central role of IRF4 in MM pathogenesis; indicate that this is an important mechanism by which lenalidomide exerts its antitumour effects; and may provide a mechanistic biomarker to predict response to lenalidomide.