Multiple myeloma cells' capacity to decompose H2O2 determines lenalidomide sensitivity

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

Research output: Contribution to journalArticle

8 Citations (Scopus)

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

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Thioredoxin-Disulfide Reductase
Multiple Myeloma
Cytotoxicity
Thioredoxins
Cells
Decomposition
Immunoglobulin Light Chains
Oxidative stress
Endoplasmic Reticulum Stress
Dimers
Peroxidase
Chemical activation
Oxidative Stress
B-Lymphocytes
Degradation
lenalidomide
Pharmaceutical Preparations
Proteins
Neoplasms
Therapeutics

ASJC Scopus subject areas

  • Immunology
  • Biochemistry
  • Hematology
  • Cell Biology

Cite this

Multiple myeloma cells' capacity to decompose H2O2 determines lenalidomide sensitivity. / Sebastian, Sinto; Zhu, Yuan X.; Braggio, Esteban D; Shi, Chang Xin; Panchabhai, Sonali C.; Van Wier, Scott A.; Ahmann, Greg J.; Chesi, Marta; Bergsagel, Peter Leif; Stewart, Alexander Keith; Fonseca, Rafael.

In: Blood, Vol. 129, No. 8, 23.02.2017, p. 991-1007.

Research output: Contribution to journalArticle

Sebastian, Sinto ; Zhu, Yuan X. ; Braggio, Esteban D ; Shi, Chang Xin ; Panchabhai, Sonali C. ; Van Wier, Scott A. ; Ahmann, Greg J. ; Chesi, Marta ; Bergsagel, Peter Leif ; Stewart, Alexander Keith ; Fonseca, Rafael. / Multiple myeloma cells' capacity to decompose H2O2 determines lenalidomide sensitivity. In: Blood. 2017 ; Vol. 129, No. 8. pp. 991-1007.
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