{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,8]],"date-time":"2026-11-08T04:53:09Z","timestamp":1794113589905,"version":"4.8.0"},"reference-count":63,"publisher":"American Society of Hematology","issue":"3","license":[{"start":{"date-parts":[[2024,1,1]],"date-time":"2024-01-01T00:00:00Z","timestamp":1704067200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2024,2,13]]},"abstract":"<jats:sec>\n                  <jats:title>Abstract<\/jats:title>\n                  <jats:p>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\u2013mass 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.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1182\/bloodadvances.2023010080","type":"journal-article","created":{"date-parts":[[2024,1,1]],"date-time":"2024-01-01T17:37:33Z","timestamp":1704130653000},"page":"785-796","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":9,"title":["Thrombospondin-1 is an endogenous substrate of cereblon responsible for immunomodulatory drug\u2013induced thromboembolism"],"prefix":"10.1182","volume":"8","author":[{"given":"Kiwamu","family":"Hatakeyama","sequence":"first","affiliation":[{"name":"1Department of Medicine and Biosystemic Sciences, Kyushu University Graduate School of Medicine, Fukuoka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshikane","family":"Kikushige","sequence":"additional","affiliation":[{"name":"1Department of Medicine and Biosystemic Sciences, Kyushu University Graduate School of Medicine, Fukuoka, Japan"},{"name":"2Center for Cellular and Molecular Medicine, Kyushu University Hospital, Fukuoka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9070-0016","authenticated-orcid":false,"given":"Daisuke","family":"Ishihara","sequence":"additional","affiliation":[{"name":"1Department of Medicine and Biosystemic Sciences, Kyushu University Graduate School of Medicine, Fukuoka, Japan"},{"name":"2Center for Cellular and Molecular Medicine, Kyushu University Hospital, Fukuoka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5313-7161","authenticated-orcid":false,"given":"Shunsuke","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"2Center for Cellular and Molecular Medicine, Kyushu University Hospital, Fukuoka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gentaro","family":"Kawano","sequence":"additional","affiliation":[{"name":"1Department of Medicine and Biosystemic Sciences, Kyushu University Graduate School of Medicine, Fukuoka, Japan"},{"name":"2Center for Cellular and Molecular Medicine, Kyushu University Hospital, Fukuoka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taro","family":"Tochigi","sequence":"additional","affiliation":[{"name":"3Miyazaki Prefectural Miyazaki Hospital, Miyazaki, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshihiro","family":"Miyamoto","sequence":"additional","affiliation":[{"name":"4Haematology\/Respiratory Medicine, Faculty of Medicine, Institute of Medical Pharmaceutical and Health Sciences, Kanazawa University Hospital, Ishikawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teppei","family":"Sakoda","sequence":"additional","affiliation":[{"name":"1Department of Medicine and Biosystemic Sciences, Kyushu University Graduate School of Medicine, Fukuoka, Japan"},{"name":"2Center for Cellular and Molecular Medicine, Kyushu University Hospital, Fukuoka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3933-1793","authenticated-orcid":false,"given":"Andy","family":"Christoforou","sequence":"additional","affiliation":[{"name":"5Bristol Myers Squibb, San Diego, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuya","family":"Kunisaki","sequence":"additional","affiliation":[{"name":"1Department of Medicine and Biosystemic Sciences, Kyushu University Graduate School of Medicine, Fukuoka, Japan"},{"name":"2Center for Cellular and Molecular Medicine, Kyushu University Hospital, Fukuoka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6201-6054","authenticated-orcid":false,"given":"Mitsuhiro","family":"Fukata","sequence":"additional","affiliation":[{"name":"1Department of Medicine and Biosystemic Sciences, Kyushu University Graduate School of Medicine, Fukuoka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koji","family":"Kato","sequence":"additional","affiliation":[{"name":"1Department of Medicine and Biosystemic Sciences, Kyushu University Graduate School of Medicine, Fukuoka, 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