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医学部 医学科 内科学講座血液・糖尿病・内分泌内科学分野 |
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論文 【 表示 ／ 非表示 】
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Integrated genetic and clinical prognostic factors for aggressive adult T-cell leukemia/lymphoma. 査読あり 国際誌
Kameda T, Kataoka K, Kamiunten A, Hidaka M, Miyoshi H, Nakano N, Nosaka K, Yoshimitsu M, Yasunaga JI, Kogure Y, Shide K, Miyahara M, Sakamoto T, Akizuki K, Hidaka T, Kubuki Y, Koya J, Kawano N, Yamashita K, Kawano H, Toyama T, Maeda K, Marutsuka K, Imaizumi Y, Kato K, Sugio T, Tokunaga M, Tashiro Y, Takaori-Kondo A, Miyazaki Y, Akashi K, Ishitsuka K, Matsuoka M, Ohshima K, Watanabe T, Kitanaka A, Utsunomiya A, Ogawa S, Shimoda K
Haematologica 108 ( 8 ) 2178 - 2191 2023年2月
担当区分：筆頭著者 記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Haematologica
The prognosis of aggressive adult T-cell leukemia/lymphoma (ATL) is poor, and allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment. In order to identify favorable prognostic patients after intensive chemotherapy, and who therefore might not require upfront allo-HSCT, we aimed to improve risk stratification of aggressive ATL patients aged <70 years. The clinical risk factors and genetic mutations were incorporated into risk modeling for overall survival (OS). We generated the m7-ATLPI, a clinicogenetic risk model for OS, that included the ATL prognostic index (PI) (ATL-PI) risk category, and non-silent mutations in seven genes, namely TP53, IRF4, RHOA, PRKCB, CARD11, CCR7, and GATA3. In the training cohort of 99 patients, the m7-ATLPI identified a low-, intermediate-, and high-risk group with 2-year OS of 100%, 43%, and 19%, respectively (hazard ratio [HR] =5.46; P<0.0001). The m7-ATLPI achieved superior risk stratification compared to the current ATL-PI (C-index 0.92 vs. 0.85, respectively). In the validation cohort of 84 patients, the m7-ATLPI defined low-, intermediate-, and high-risk groups with a 2-year OS of 81%, 30%, and 0%, respectively (HR=2.33; P=0.0094), and the model again outperformed the ATL-PI (C-index 0.72 vs. 0.70, respectively). The simplified m7-ATLPI, which is easier to use in clinical practice, achieved superior risk stratification compared to the ATLPI, as did the original m7-ATLPI; the simplified version was calculated by summing the following: high-risk ATL-PI category (+10), low-risk ATL-PI category (−4), and non-silent mutations in TP53 (+4), IRF4 (+3), RHOA (+1), PRKCB (+1), CARD11 (+0.5), CCR7 (−2), and GATA3 (−3).
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Kameda T., Shide K., Kamiunten A., Kogure Y., Morishita D., Koya J., Tahira Y., Akizuki K., Yokomizo-Nakano T., Kubota S., Marutsuka K., Sekine M., Hidaka T., Kubuki Y., Kitai Y., Matsuda T., Yoda A., Ohshima T., Sugiyama M., Sashida G., Kataoka K., Ogawa S., Shimoda K.
Communications Biology 5 ( 1 ) 1309 - 1309 2022年12月
担当区分：筆頭著者 記述言語：日本語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Communications Biology
Adult T-cell leukemia/lymphoma (ATL) is caused by human T-cell leukemia virus type 1 (HTLV-1). In addition to HTLV-1 bZIP factor (HBZ), a leukemogenic antisense transcript of HTLV-1, abnormalities of genes involved in TCR-NF-κB signaling, such as CARD11, are detected in about 90% of patients. Utilizing mice expressing CD4+ T cell-specific CARD11(E626K) and/or CD4+ T cell-specific HBZ, namely CARD11(E626K)CD4-Cre mice, HBZ transgenic (Tg) mice, and CARD11(E626K)CD4-Cre;HBZ Tg double transgenic mice, we clarify these genes’ pathogenetic effects. CARD11(E626K)CD4-Cre and HBZ Tg mice exhibit lymphocytic invasion to many organs, including the lungs, and double transgenic mice develop lymphoproliferative disease and increase CD4+ T cells in vivo. CARD11(E626K) and HBZ cooperatively activate the non-canonical NF-κB pathway, IRF4 targets, BATF3/IRF4/HBZ transcriptional network, MYC targets, and E2F targets. Most KEGG and HALLMARK gene sets enriched in acute-type ATL are also enriched in double transgenic mice, indicating that these genes cooperatively contribute to ATL development.
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Whole-genome landscape of adult T-cell leukemia/lymphoma 査読あり 国際誌
Kogure Y., Kameda T., Koya J., Yoshimitsu M., Nosaka K., Yasunaga J.i., Imaizumi Y., Watanabe M., Saito Y., Ito Y., McClure M.B., Tabata M., Shingaki S., Yoshifuji K., Chiba K., Okada A., Kakiuchi N., Nannya Y., Kamiunten A., Tahira Y., Akizuki K., Sekine M., Shide K., Hidaka T., Kubuki Y., Kitanaka A., Hidaka M., Nakano N., Utsunomiya A., Sica R.A., Acuna-Villaorduna A., Janakiram M., Shah U., Ramos J.C., Shibata T., Takeuchi K., Takaori-Kondo A., Miyazaki Y., Matsuoka M., Ishitsuka K., Shiraishi Y., Miyano S., Ogawa S., Ye B.H., Shimoda K., Kataoka K.
Blood 139 ( 7 ) 967 - 982 2022年2月
担当区分：筆頭著者 記述言語：日本語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Blood
Adult T-cell leukemia/lymphoma (ATL) is an aggressive neoplasm immunophenotypically resembling regulatory T cells, associated with human T-cell leukemia virus type-1. Here, we performed whole-genome sequencing (WGS) of 150 ATL cases to reveal the overarching landscape of genetic alterations in ATL. We discovered frequent (33%) loss-of-function alterations preferentially targeting the CIC long isoform, which were overlooked by previous exome-centric studies of various cancer types. Long but not short isoform–specific inactivation of Cic selectively increased CD4+CD25+Foxp3+ T cells in vivo. We also found recurrent (13%) 3′-truncations of REL, which induce transcriptional upregulation and generate gain-of-function proteins. More importantly, REL truncations are also common in diffuse large B-cell lymphoma, especially in germinal center B-cell–like subtype (12%). In the non-coding genome, we identified recurrent mutations in regulatory elements, particularly splice sites, of several driver genes. In addition, we characterized the different mutational processes operative in clustered hypermutation sites within and outside immunoglobulin/T-cell receptor genes and identified the mutational enrichment at the binding sites of host and viral transcription factors, suggesting their activities in ATL. By combining the analyses for coding and noncoding mutations, structural variations, and copy number alterations, we discovered 56 recurrently altered driver genes, including 11 novel ones. Finally, ATL cases were classified into 2 molecular groups with distinct clinical and genetic characteristics based on the driver alteration profile. Our findings not only help to improve diagnostic and therapeutic strategies in ATL, but also provide insights into T-cell biology and have implications for genome-wide cancer driver discovery.
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Single-Cell Analysis of the Multicellular Ecosystem in Viral Carcinogenesis by HTLV-1. 査読あり
Koya J, Saito Y, Kameda T, Kogure Y, Yuasa M, Nagasaki J, McClure MB, Shingaki S, Tabata M, Tahira Y, Akizuki K, Kamiunten A, Sekine M, Shide K, Kubuki Y, Hidaka T, Kitanaka A, Nakano N, Utsunomiya A, Togashi Y, Ogawa S, Shimoda K, Kataoka K
Blood cancer discovery 2 ( 5 ) 450 - 467 2021年9月
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Effects of tucidinostat in adult T-cell leukemia/lymphoma in clinical practice 査読あり
Kamiunten A., Kameda T., Sekine M., Kawano H., Toyama T., Akizuki K., Kawano N., Maeda K., Sato S., Takeuchi M., Ishizaki J., Nagamine K., Kuroki A., Ikeda R., Matsumoto K., Karasawa M., Tahira Y., Uchida T., Shimoda H., Hidaka T., Yamashita K., Yamaguchi H., Kubuki Y., Shimoda K., Shide K.
International Journal of Hematology 2025年
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：International Journal of Hematology
Adult T-cell leukemia/lymphoma (ATL) is a peripheral T-cell malignancy with a poor prognosis. We conducted a retrospective study across six institutions in Miyazaki Prefecture, Japan, to assess the efficacy of tucidinostat in patients with relapsed/refractory ATL who had not undergone transplantation. Between October 2021 and July 2023, 24 patients aged 41 to 88 years (median, 73.4 years) who had undergone prior therapies, including intensive chemotherapy (79.2%) and mogamulizumab immunotherapy (79.2%), received tucidinostat. Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) were evaluated as key outcomes. ORR and DCR reached 54.2% and 91.7%, respectively. The median PFS was 3.95 months, and OS was 8.04 months, which were not inferior to the results of a phase IIb study. The influential factors for PFS were age ≥ 75 years and high soluble IL-2 receptor (sIL-2R) levels above 5000 U/mL at the start of treatment. Favorable patients without these factors achieved a PFS of 11.4 months. Treatment-related adverse events were mainly hematologic but were managed over the course of treatment. Our findings indicate that tucidinostat provides survival benefits in patients with relapsed/refractory ATL in clinical practice and highlight key clinical factors for better outcomes.
書籍等出版物 【 表示 ／ 非表示 】
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実践! IBD 診療
山本章二朗， 三池忠，安倍弘生，下田和哉（ 担当： 共著 , 範囲: 198-199）
医学出版 2014年5月
記述言語：日本語 著書種別：学術書
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実践! IBD 診療
山本章二朗， 三池忠，安倍弘生，下田和哉（ 担当： 共著 , 範囲: 198-199）
医学出版 2014年5月
記述言語：日本語 著書種別：学術書
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実践! IBD 診療
山本章二朗， 三池忠，安倍弘生，下田和哉（ 担当： 共著 , 範囲: 198-199）
医学出版 2014年5月
記述言語：日本語 著書種別：学術書
MISC 【 表示 ／ 非表示 】
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Shide K., Takenaka K., Kitanaka A., Numata A., Kameda T., Yamauchi T., Inagaki A., Mizuno S., Takami A., Ito S., Hagihara M., Usuki K., Maekawa T., Sunami K., Ueda Y., Tsutsui M., Ando M., Komatsu N., Ozawa K., Kurokawa M., Arai S., Mitani K., Akashi K., Shimoda K.
Blood Cancer Journal 13 ( 1 ) 110 - 110 2023年12月
記述言語：英語 掲載種別：速報，短報，研究ノート等（学術雑誌） 出版者・発行元：Blood Cancer Journal
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Preclinical Evaluation of a Novel MALT1 Inhibitor CTX-177 for Relapse/Refractory Lymphomas 査読あり
Daisuke Morishita, Akio Mizutani, Hirokazu Tozaki, Yasuyoshi Arikawa, Takuro Kameda, Ayako Kamiunten, Keisuke Kataoka, Akinori Yoda, Yotaro Ochi, Kotaro Shide, Koji Izutsu, Yosuke Minami, Kazuya Shimoda, Hiroshi Miyake, Seishi Ogawa
BLOOD 136 2020年11月
科研費（文科省・学振・厚労省）獲得実績 【 表示 ／ 非表示 】
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ATL発症マウスモデルの作成と腫瘍生存シグナルの多様性を考慮した精密医療の確立
研究課題/領域番号：23K07840 2023年04月 - 2026年03月
独立行政法人日本学術振興会 科学研究費基金 基盤研究(C)
亀田 拓郎
担当区分：研究代表者
成人T細胞白血/リンパ腫（ATL）は、レトロウイルスであるヒトT細胞白血病ウイルス1型(HTLV-1)が感染したCD4陽性T細胞が腫瘍化する疾患である。これまでに感染細胞に発現するプロウイルス遺伝子HBZと、感染後に獲得されるCARD11変異に代表されるT細胞抗原受容体(TCR)-NF-κB経路の遺伝子異常が協調し、ATLの発症前段階といえる状態を作り出すことを見出している。本研究では、発症前段階からATL発症の間に存在するイベントを明らかにし、ATL発症マウスモデルの作成を目指す。また、ATL細胞が依存する生存シグナルの多様性に着目し、ATLに対するプレシジョンメディシンの概念実証(proof of concept)を試みる。
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テーマ１：ATL発症前段階から発症に必要なイベントの解明と、ATL発症マウスモデル作成・・・HBZとCARD11変異の両者を有する２重異常マウスの研究で急性転化に必要であることが示唆されたNOTCH1変異、または、HBZとCARD11変異により誘導されるBATF3/IRF4/HBZ転写ネットワークを増強し更なるNF-κB経路の活性化をもたらすと推測されるIRF4変異を、２重異常CD4陽性T細胞へ導入した。３～４重遺伝子異常を発現するCD4陽性T細胞の動態を解析中である。
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テーマ２：ATL細胞が依存する生存シグナルの多様性に合わせたプレシジョンメディシンのコンセプト確立・・・収集したATL細胞株17種類の遺伝子変異を明らかにした。TCRNF-κB経路阻害剤（MALT1阻害剤）、新規臨床承認薬であるEZH1/2阻害剤、HDAC阻害剤、既存抗がん剤VCRの単独または併用による in vitro 増殖抑制試験を行い。各々の腫瘍の変異プロファイルと、各阻害剤への反応を比較検討した。 -
遺伝子改変マウスを用いたHTLV-1関連疾患の病態解明および新規治療法探索
研究課題/領域番号：17K09931 2017年04月 - 2020年03月
科学研究費補助金 基盤研究(C)
担当区分：研究代表者
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骨髄増殖性腫瘍における重複遺伝子異常の意義及び急性転化メカニズムの解明
研究課題/領域番号：15K19554 2015年04月 - 2017年03月
科学研究費補助金 若手研究(B)
担当区分：研究代表者