Multiple myeloma cells' capacity to decompose H2O2 determines lenalidomide sensitivity

Sinto Sebastian, Yuan X. Zhu, Esteban Braggio, Chang Xin Shi, Sonali C. Panchabhai, Scott A. Van Wier, Greg J. Ahmann, Marta Chesi, P. Leif Bergsagel, A. Keith Stewart, Rafael Fonseca

Research output: Contribution to journalArticle

13 Scopus citations

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 H2O2 decomposition in MM cells. MM cells with lower H2O2-decomposition capacity were more vulnerable to lenalidomide-induced H2O2 accumulation and associated cytotoxicity. CRBN-dependent degradation of IKZF1 and IKZF3 was a consequence of H2O2-mediated oxidative stress. Lenalidomide increased intracellular H2O2 levels 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.

Original languageEnglish (US)
Pages (from-to)991-1007
Number of pages17
JournalBlood
Volume129
Issue number8
DOIs
StatePublished - Feb 23 2017

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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