title: Multiple myeloma cells' capacity to decompose H2O2determines lenalidomide sensitivity.
abstract: Lenalidomide is an immunomodulatory drug (IMiDs) with clinical efficacy in multiple myeloma (MM) and other late B-cell neoplasms. Although cereblon (CRBN) is an essential requirement for IMiD action, the complete molecular and biochemical mechanisms responsible for lenalidomide-mediated sensitivity or resistance remain unknown. Here, we report that IMiDs work primarily via inhibition of peroxidase-mediated intracellular H2O2decomposition in MM cells. MM cells with lower H2O2-decomposition capacity were more vulnerable to lenalidomide-induced H2O2accumulation and associated cytotoxicity. CRBN-dependent degradation of IKZF1 and IKZF3 was a consequence of H2O2-mediated oxidative stress. Lenalidomide increased intracellular H2O2levels by inhibiting thioredoxin reductase (TrxR) in cells expressing CRBN, causing accumulation of immunoglobulin light-chain dimers, significantly increasing endoplasmic reticulum stress and inducing cytotoxicity by activation of BH3-only protein Bim in MM. Other direct inhibitors of TrxR and thioredoxin (Trx) caused similar cytotoxicity, but in a CRBN-independent fashion. Our findings could help identify patients most likely to benefit from IMiDs and suggest direct TrxR or Trx inhibitors for MM therapy.
authors.affiliation: Division of Hematology and Medical Oncology, Mayo Clinic, Scottsdale, AZ.
authors.forename: Sinto
authors.initials: S
authors.lastname: Sebastian
authors.affiliation: Division of Hematology and Medical Oncology, Mayo Clinic, Scottsdale, AZ.
authors.forename: Yuan X
authors.initials: YX
authors.lastname: Zhu
authors.affiliation: Division of Hematology and Medical Oncology, Mayo Clinic, Scottsdale, AZ.
authors.forename: Esteban
authors.initials: E
authors.lastname: Braggio
authors.affiliation: Division of Hematology and Medical Oncology, Mayo Clinic, Scottsdale, AZ.
authors.forename: Chang-Xin
authors.initials: CX
authors.lastname: Shi
authors.affiliation: Division of Hematology and Medical Oncology, Mayo Clinic, Scottsdale, AZ.
authors.forename: Sonali C
authors.initials: SC
authors.lastname: Panchabhai
authors.affiliation: Division of Hematology and Medical Oncology, Mayo Clinic, Scottsdale, AZ.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Van Wier
authors.affiliation: Division of Hematology and Medical Oncology, Mayo Clinic, Scottsdale, AZ.
authors.forename: Greg J
authors.initials: GJ
authors.lastname: Ahmann
authors.affiliation: Division of Hematology and Medical Oncology, Mayo Clinic, Scottsdale, AZ.
authors.forename: Marta
authors.initials: M
authors.lastname: Chesi
authors.affiliation: Division of Hematology and Medical Oncology, Mayo Clinic, Scottsdale, AZ.
authors.forename: P Leif
authors.initials: PL
authors.lastname: Bergsagel
authors.affiliation: Division of Hematology and Medical Oncology, Mayo Clinic, Scottsdale, AZ.
authors.forename: A Keith
authors.initials: AK
authors.lastname: Stewart
authors.affiliation: Division of Hematology and Medical Oncology, Mayo Clinic, Scottsdale, AZ.
authors.forename: Rafael
authors.initials: R
authors.lastname: Fonseca
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D051740:Ikaros Transcription Factor / Q000378:metabolism; D007155:Immunologic Factors / Q000494:pharmacology*; D000077269:Lenalidomide; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D010447:Peptide Hydrolases / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C502543:CRBN protein, human; C497239:IKZF1 protein, human; C106285:IKZF3 protein, human; D007155:Immunologic Factors; D051740:Ikaros Transcription Factor; D013792:Thalidomide; D006861:Hydrogen Peroxide; D009195:Peroxidase; D044767:Ubiquitin-Protein Ligases; D010447:Peptide Hydrolases; D000077269:Lenalidomide