title: Lenalidomide downregulates the cell survival factor, interferon regulatory factor-4, providing a potential mechanistic link for predicting response.
abstract: 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.
authors.affiliation: Translational Development Department, Celgene, San Diego, CA 92122, USA. alopez@celgene.com
authors.forename: Antonia
authors.initials: A
authors.lastname: Lopez-Girona
authors.forename: Daniel
authors.initials: D
authors.lastname: Heintel
authors.forename: Ling-Hua
authors.initials: LH
authors.lastname: Zhang
authors.forename: Derek
authors.initials: D
authors.lastname: Mendy
authors.forename: Svetlana
authors.initials: S
authors.lastname: Gaidarova
authors.forename: Helen
authors.initials: H
authors.lastname: Brady
authors.forename: Justin Blake
authors.initials: JB
authors.lastname: Bartlett
authors.forename: Peter H
authors.initials: PH
authors.lastname: Schafer
authors.forename: Martin
authors.initials: M
authors.lastname: Schreder
authors.forename: Arnold
authors.initials: A
authors.lastname: Bolomsky
authors.forename: Bernadette
authors.initials: B
authors.lastname: Hilgarth
authors.forename: Niklas
authors.initials: N
authors.lastname: Zojer
authors.forename: Heinz
authors.initials: H
authors.lastname: Gisslinger
authors.forename: Heinz
authors.initials: H
authors.lastname: Ludwig
authors.forename: Tom
authors.initials: T
authors.lastname: Daniel
authors.forename: Ulrich
authors.initials: U
authors.lastname: Jäger
authors.forename: Rajesh
authors.initials: R
authors.lastname: Chopra
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000096:biosynthesis* / Q000235:genetics; D049109:Cell Proliferation; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D016259:Genes, myc; D006801:Humans; D050835:Interferon Regulatory Factors / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D000077269:Lenalidomide; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D011379:Prognosis; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D000099218:Interferon Regulatory Factor-4
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D050835:Interferon Regulatory Factors; D000077269:Lenalidomide; D009363:Neoplasm Proteins; D013792:Thalidomide; D000099218:Interferon Regulatory Factor-4