title: Lenalidomide inhibits the proliferation of CLL cells via a cereblon/p21(WAF1/Cip1)-dependent mechanism independent of functional p53.
abstract: Lenalidomide has demonstrated clinical activity in patients with chronic lymphocytic leukemia (CLL), even though it is not cytotoxic for primary CLL cells in vitro. We examined the direct effect of lenalidomide on CLL-cell proliferation induced by CD154-expressing accessory cells in media containing interleukin-4 and -10. Treatment with lenalidomide significantly inhibited CLL-cell proliferation, an effect that was associated with the p53-independent upregulation of the cyclin-dependent kinase inhibitor, p21(WAF1/Cip1) (p21). Silencing p21 with small interfering RNA impaired the capacity of lenalidomide to inhibit CLL-cell proliferation. Silencing cereblon, a known molecular target of lenalidomide, impaired the capacity of lenalidomide to induce expression of p21, inhibit CD154-induced CLL-cell proliferation, or enhance the degradation of Ikaros family zinc finger proteins 1 and 3. We isolated CLL cells from the blood of patients before and after short-term treatment with low-dose lenalidomide (5 mg per day) and found the leukemia cells were also induced to express p21 in vivo. These results indicate that lenalidomide can directly inhibit proliferation of CLL cells in a cereblon/p21-dependent but p53-independent manner, at concentrations achievable in vivo, potentially contributing to the capacity of this drug to inhibit disease-progression in patients with CLL.
authors.affiliation: Moores Cancer Center, University of California, San Diego, La Jolla, CA; and.
authors.forename: Jessie-F
authors.initials: JF
authors.lastname: Fecteau
authors.affiliation: Department of Biochemistry and Structural Biology, Celgene Corporation, San Diego, CA.
authors.forename: Laura G
authors.initials: LG
authors.lastname: Corral
authors.affiliation: Moores Cancer Center, University of California, San Diego, La Jolla, CA; and.
authors.forename: Emanuela M
authors.initials: EM
authors.lastname: Ghia
authors.affiliation: Department of Biochemistry and Structural Biology, Celgene Corporation, San Diego, CA.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Gaidarova
authors.affiliation: Moores Cancer Center, University of California, San Diego, La Jolla, CA; and.
authors.forename: Diahnn
authors.initials: D
authors.lastname: Futalan
authors.affiliation: Moores Cancer Center, University of California, San Diego, La Jolla, CA; and.
authors.forename: Ila Sri
authors.initials: IS
authors.lastname: Bharati
authors.affiliation: Department of Biochemistry and Structural Biology, Celgene Corporation, San Diego, CA.
authors.forename: Brian
authors.initials: B
authors.lastname: Cathers
authors.affiliation: Moores Cancer Center, University of California, San Diego, La Jolla, CA; and.
authors.forename: Maria
authors.initials: M
authors.lastname: Schwaederlé
authors.affiliation: Moores Cancer Center, University of California, San Diego, La Jolla, CA; and.
authors.forename: Bing
authors.initials: B
authors.lastname: Cui
authors.affiliation: Department of Biochemistry and Structural Biology, Celgene Corporation, San Diego, CA.
authors.forename: Antonia
authors.initials: A
authors.lastname: Lopez-Girona
authors.affiliation: Moores Cancer Center, University of California, San Diego, La Jolla, CA; and.
authors.forename: Davorka
authors.initials: D
authors.lastname: Messmer
authors.affiliation: Moores Cancer Center, University of California, San Diego, La Jolla, CA; and.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Kipps
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000502:physiology*; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D000077269:Lenalidomide; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism / Q000473:pathology*; D010447:Peptide Hydrolases / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D044767:Ubiquitin-Protein Ligases
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D020533:Angiogenesis Inhibitors; C493956:CDKN1A protein, human; C502543:CRBN protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016159:Tumor Suppressor Protein p53; D013792:Thalidomide; D044767:Ubiquitin-Protein Ligases; D010447:Peptide Hydrolases; D000077269:Lenalidomide