title: Responsiveness of cytogenetically discrete human myeloma cell lines to lenalidomide: lack of correlation with cereblon and interferon regulatory factor 4 expression levels.
abstract: The introduction of novel immunomodulatory drugs (IMiDs) has dramatically improved the survival of patients with multiple myeloma (MM). While it has been shown that patients with specific cytogenetic subtypes, namely t(4;14), have the best outcomes when treated with bortezomib-based regimens, the relationship between cytogenetic subtypes and response to IMiDs remains unclear. Using DNA synthesis assays, we investigated the relationship between cytogenetic subtype and lenalidomide response in a representative panel of human myeloma cell lines (HMCLs). We examined HMCL protein expression levels of the lenalidomide target cereblon (CRBN) and its downstream target interferon regulatory factor-4 (IRF4), which have previously been shown to be predictive of lenalidomide response in HMCLs. Our results reveal that lenalidomide response did not correlate with specific cytogenetic translocations. There were distinct groups of lenalidomide-responsive and non-responsive HMCLs, as defined by inhibition of cellular proliferation; notably, all of the hyperdiploid HMCLs fell into the latter category. Repeated dosing of lenalidomide significantly lowered the IC50 of the responsive HMCL ALMC-1 (IC50 = 2.6 μm vs. 0.005 μm, P < 0.0001), but did not have an effect on the IC50 of the non-responsive DP-6 HMCL (P > 0.05). Moreover, no association was found between lenalidomide responsiveness and CRBN and IRF4 expression. Our data indicate that lenalidomide sensitivity is independent of cytogenetic subtype in HMCLs. While CRBN and IRF4 have been shown to be associated with response to lenalidomide in patients, these findings do not translate back to HMCLs, which could be attributable to factors present in the bone marrow microenvironment.
authors.affiliation: Center for Translational Science Activities, Mayo Clinic, Rochester, MN, USA.|Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
authors.forename: Alexandra J
authors.initials: AJ
authors.lastname: Greenberg
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Denise K
authors.initials: DK
authors.lastname: Walters
authors.affiliation: Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: Shaji K
authors.initials: SK
authors.lastname: Kumar
authors.affiliation: Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: S Vincent
authors.initials: SV
authors.lastname: Rajkumar
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, MN, USA.|Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: Diane F
authors.initials: DF
authors.lastname: Jelinek
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002869:Chromosome Aberrations; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology*; D050835:Interferon Regulatory Factors / Q000235:genetics* / Q000378:metabolism; D000077269:Lenalidomide; D009101:Multiple Myeloma / Q000188:drug therapy / Q000235:genetics*; D010447:Peptide Hydrolases / Q000235:genetics*; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases; D000099218:Interferon Regulatory Factor-4
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D007155:Immunologic Factors; D050835:Interferon Regulatory Factors; D000077269:Lenalidomide; D010447:Peptide Hydrolases; D013792:Thalidomide; D044767:Ubiquitin-Protein Ligases; D000099218:Interferon Regulatory Factor-4; C502543:CRBN protein, human
keywords: CRBN; IRF4; cytogenetics; lenalidomide; multiple myeloma