Aromatase is a novel neosubstrate of cereblon responsible for immunomodulatory drug-induced thrombocytopenia

Taro Tochigi, Toshihiro Miyamoto, Kiwamu Hatakeyama, Teppei Sakoda, Daisuke Ishihara, Hidetoshi Irifune, Takahiro Shima, Koji Kato, Takahiro Maeda, Takumi Ito, Hiroshi Handa, Koichi Akashi, Yoshikane Kikushige

研究成果: Contribution to journalArticle

1 被引用数 (Scopus)

抄録

Immunomodulatory drugs (IMiDs) are key agents for the treatment of multiple myeloma and myelodysplastic syndrome with chromosome 5q deletion. IMiDs exert their pleiotropic effects through the recruitment of neosubstrates to cereblon, a substrate receptor of the E3 ubiquitin ligase complex; therefore, identification of cell-specific neosubstrates is important to understand the effects of IMiDs. In clinical practice, IMiDs induce thrombocytopenia, which frequently results in the discontinuation of IMiD treatment. In the current study, we sought to identify the molecular mechanism underlying thrombocytopenia induced by IMiD treatment. We found that IMiDs strongly impaired proplatelet formation, a critical step in functional platelet production, through the inhibition of autocrine estradiol signaling in human megakaryocytes. Furthermore, we identified aromatase, an indispensable enzyme for estradiol biosynthesis, as a novel neosubstrate of cereblon. IMiDs promoted the recruitment of aromatase to cereblon, resulting in the degradation of aromatase in a proteasome-dependent manner. Finally, aromatase was significantly degraded in the bone marrow of patients with multiple myeloma who developed thrombocytopenia with IMiD treatment. These data suggest that aromatase is a neosubstrate of cereblon that is responsible for IMiD-induced thrombocytopenia.

本文言語英語
ページ(範囲)2146-2158
ページ数13
ジャーナルBlood
135
24
DOI
出版ステータス出版済み - 6 11 2020

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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