PMID- 38344143 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20240213 IS - 2234-943X (Print) IS - 2234-943X (Electronic) IS - 2234-943X (Linking) VI - 13 DP - 2023 TI - IMiD/CELMoD-induced growth suppression of adult T-cell leukemia/lymphoma cells via cereblon through downregulation of target proteins and their downstream effectors. PG - 1272528 LID - 10.3389/fonc.2023.1272528 [doi] LID - 1272528 AB - Adult T-cell leukemia/lymphoma (ATL) is an aggressive T-cell neoplasia associated with human T-cell leukemia virus type 1 (HTLV-1) infection and has an extremely poor prognosis. Lenalidomide (LEN; a second-generation immunomodulatory drug [IMiD]) has been employed as an additional therapeutic option for ATL since 2017, but its mechanism of action has not been fully proven, and recent studies reported emerging concerns about the development of second primary malignancies in patients treated with long-term IMiD therapy. Our purpose in this study was to elucidate the IMiD-mediated anti-ATL mechanisms. Thirteen ATL-related cell lines were divided into LEN-sensitive or LEN-resistant groups. CRBN knockdown (KD) led to a loss of LEN efficacy and IKZF2-KD-induced LEN efficacy in resistant cells. DNA microarray analysis demonstrated distinct transcriptional alteration after LEN treatment between LEN-sensitive and LEN-resistant ATL cell lines. Oral treatment of LEN for ATL cell-transplanted severe combined immunodeficiency (SCID) mice also indicated clear suppressive effects on tumor growth. Finally, a novel cereblon modulator (CELMoD), iberdomide (IBE), exhibited a broader and deeper spectrum of growth suppression to ATL cells with efficient IKZF2 degradation, which was not observed in other IMiD treatments. Based on these findings, our study strongly supports the novel therapeutic advantages of IBE against aggressive and relapsed ATL. CI - Copyright (c) 2024 Wang, Shimosaki, Ikebe, Iha, Yamamoto, Fife, Ichikawa, Hori, Ogata, Tsukamoto, Hijiya, Moriyama, Hagiwara, Kusano, Saito, Ahmed, Nishizono, Handa and Morishita. FAU - Wang, Yu AU - Wang Y AD - Department of Microbiology, Faculty of Medicine, Oita University, Yufu, Japan. FAU - Shimosaki, Shunsuke AU - Shimosaki S AD - Division of Tumor and Cellular Biochemistry, Department of Medical Sciences, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan. FAU - Ikebe, Emi AU - Ikebe E AD - Department of Microbiology, Faculty of Medicine, Oita University, Yufu, Japan. AD - Research Center for Biological Products in the Next Generation, National Institute of Infectious Diseases, Musashi-murayama, Japan. FAU - Iha, Hidekatsu AU - Iha H AD - Department of Microbiology, Faculty of Medicine, Oita University, Yufu, Japan. AD - Division of Pathophysiology, The Research Center for GLOBAL and LOCAL Infectious Diseases (RCGLID), Oita University, Yufu, Japan. AD - Borneo Medical and Health Research Centre, Faculty of Medicine and Health Sciences, University of Malaysia Sabah, Kota Kinabalu, Malaysia. FAU - Yamamoto, Jun-Ichi AU - Yamamoto JI AD - Department of Nanoparticle Translational Research, Tokyo Medical University, Tokyo, Japan. FAU - Fife, Nichole AU - Fife N AD - Department of Microbiology, Faculty of Medicine, Oita University, Yufu, Japan. FAU - Ichikawa, Tomonaga AU - Ichikawa T AD - Division of Tumor and Cellular Biochemistry, Department of Medical Sciences, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan. FAU - Hori, Mitsuo AU - Hori M AD - Department of Hematology, Ibaraki Prefectural Central Hospital, Kasama, Japan. FAU - Ogata, Masao AU - Ogata M AD - Division of Pathophysiology, The Research Center for GLOBAL and LOCAL Infectious Diseases (RCGLID), Oita University, Yufu, Japan. AD - Department of Hematology and Oncology, Faculty of Medicine, Oita University, Yufu, Japan. FAU - Tsukamoto, Yoshiyuki AU - Tsukamoto Y AD - Department of Molecular Pathology, Faculty of Medicine, Oita University, Yufu, Japan. FAU - Hijiya, Naoki AU - Hijiya N AD - Department of Molecular Pathology, Faculty of Medicine, Oita University, Yufu, Japan. FAU - Moriyama, Masatsugu AU - Moriyama M AD - Department of Molecular Pathology, Faculty of Medicine, Oita University, Yufu, Japan. FAU - Hagiwara, Shotaro AU - Hagiwara S AD - Mito Center for Regional Medical Education, University of Tsukuba, Ibaraki, Japan. FAU - Kusano, Shuichi AU - Kusano S AD - Division of Biological Information Technology, Joint Research Center for Human Retrovirus Infection, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan. FAU - Saito, Masumichi AU - Saito M AD - Research Center for Biological Products in the Next Generation, National Institute of Infectious Diseases, Musashi-murayama, Japan. FAU - Ahmed, Kamruddin AU - Ahmed K AD - Borneo Medical and Health Research Centre, Faculty of Medicine and Health Sciences, University of Malaysia Sabah, Kota Kinabalu, Malaysia. FAU - Nishizono, Akira AU - Nishizono A AD - Department of Microbiology, Faculty of Medicine, Oita University, Yufu, Japan. AD - Division of Pathophysiology, The Research Center for GLOBAL and LOCAL Infectious Diseases (RCGLID), Oita University, Yufu, Japan. FAU - Handa, Hiroshi AU - Handa H AD - Department of Nanoparticle Translational Research, Tokyo Medical University, Tokyo, Japan. FAU - Morishita, Kazuhiro AU - Morishita K AD - Division of Tumor and Cellular Biochemistry, Department of Medical Sciences, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan. LA - eng PT - Journal Article DEP - 20240124 PL - Switzerland TA - Front Oncol JT - Frontiers in oncology JID - 101568867 PMC - PMC10853999 OTO - NOTNLM OT - CRBN OT - HTLV-1 OT - IKZF2 OT - IRF4 OT - adult T-cell lymphoma/leukemia OT - cereblon modulator (CELMoD) OT - immunomodulatory drug (IMiDs) COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. This study was partly funded by Bristol-Myers Squibb. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision. EDAT- 2024/02/12 15:42 MHDA- 2024/02/12 15:43 PMCR- 2023/01/01 CRDT- 2024/02/12 04:17 PHST- 2023/08/04 00:00 [received] PHST- 2023/12/18 00:00 [accepted] PHST- 2024/02/12 15:43 [medline] PHST- 2024/02/12 15:42 [pubmed] PHST- 2024/02/12 04:17 [entrez] PHST- 2023/01/01 00:00 [pmc-release] AID - 10.3389/fonc.2023.1272528 [doi] PST - epublish SO - Front Oncol. 2024 Jan 24;13:1272528. doi: 10.3389/fonc.2023.1272528. eCollection 2023.