| 1. |
Kiwamu Hatakeyama, Yoshikane Kikushige, Daisuke Ishihara, Shunsuke Yamamoto, Gentaro Kawano, Taro Tochigi, Toshihiro Miyamoto, Teppei Sakoda, Andy Christoforou, Yuya Kunisaki, Mitsuhiro Fukata, Koji Kato, Takumi Ito, Hiroshi Handa, Koichi Akashi, Thrombospondin-1 is an endogenous substrate of cereblon responsible for immunomodulatory drug–induced thromboembolism, blood advances, 10.1182/bloodadvances.2023010080., 8, 3, 785-796, 2024.02, Immunomodulatory drugs (IMiDs) are key drugs for treating multiple myeloma and myelodysplastic syndrome with chromosome 5q deletion. IMiDs exert their pleiotropic effects through the interaction between cell-specific substrates and cereblon, a substrate receptor of the E3 ubiquitin ligase complex. Thus, identification of cell-specific substrates is important for understanding the effects of IMiDs. IMiDs increase the risk of thromboembolism, which sometimes results in fatal clinical outcomes. In this study, we sought to clarify the molecular mechanisms underlying IMiDs-induced thrombosis. We investigated cereblon substrates in human megakaryocytes using liquid chromatography–mass spectrometry and found that thrombospondin-1 (THBS-1), which is an inhibitor of a disintegrin-like and metalloproteinase with thrombospondin type 1 motifs 13, functions as an endogenous substrate in human megakaryocytes. IMiDs inhibited the proteasomal degradation of THBS-1 by impairing the recruitment of cereblon to THBS-1, leading to aberrant accumulation of THBS-1. We observed a significant increase in THBS-1 in peripheral blood mononuclear cells as well as larger von Willebrand factor multimers in the plasma of patients with myeloma, who were treated with IMiDs. These results collectively suggest that THBS-1 represents an endogenous substrate of cereblon. This pairing is disrupted by IMiDs, and the aberrant accumulation of THBS-1 plays an important role in the pathogenesis of IMiDs-induced thromboembolism.. |
| 2. |
Kiwamu Hatakeyama, Michinari Hieda, Yuichiro Semba, Shohei Moriyama, Yuqing Wang, Takahiro Maeda, Koji Kato, Toshihiro Miyamoto, Koichi Akashi, Yoshikane Kikushige, TET2 Clonal Hematopoiesis is Associated with Anthracycline-Induced Cardiotoxicity in
Patients with Lymphoma, J Am Coll Cardiol CardioOnc. 2022 Mar, 4 (1) 141–143., 10.1016/j.jaccao.2022.01.098, 4, 1, 141-143, 2022 Mar, 4 (1) 141–143., 2022.03.  |
