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• Gene expression profile of adult T-cell leukemia/lymphoma with human T-cell lymphotropic virus type 1-infected Hodgkin and Reed-Sternberg-like cells is more similar to classic Hodgkin lymphoma than typical adult T-cell leukemia/lymphoma.

  Miyagi S, Mori K, Miyawaki K, Shimo M, Tamaki T, Sakihama S, Takatori M, Akashi K, Karube K, Kato K

  Haematologica     2026年04月 [ 査読有り ]

  掲載種別: 研究論文（学術雑誌）

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• Integrated genetic analyses identified T-cell neoplasms other than adult T-cell leukemia/lymphoma in HTLV-1 carriers.

  Naito Y, Yasuda T, Sakihama S, Aiba M, Morichika K, Miyazaki K, Imai H, Masaki A, Tsuyuki T, Shimada S, Yoshimitsu M, Aoyama H, Nakada N, Miyagi T, Tamaki T, Chen BJ, Yuan CT, Fukushima T, Chuang SS, Karube K

  Blood advances ( Blood Advances )  10 ( 5 ) 1670 - 1674   2026年03月 [ 査読有り ]

  掲載種別: 研究論文（学術雑誌）

  　概要を見る

  Adult T-cell leukemia/lymphoma (ATLL) is a mature T-cell neoplasm caused by human T-cell leukemia virus type 1 (HTLV-1) infection. Although most T-cell neoplasms that develop in HTLV-1 carriers are considered ATLL, non-ATLL T-cell lymphomas (TCLs) could also occur, as documented in only a few case reports. Herein, we presented 14 cases of non-ATLL TCLs arising in HTLV-1 carriers. All TCL cases were serologically positive for HTLV-1 antibody; Southern blot analysis for the viral integration of HTLV-1, in situ hybridization for HTLV-1 basic leucine zipper factor (HBZ-ISH), quantitative real-time PCR for HTLV-1 proviral load (HTLV-1-qPCR), the entire HTLV-1 genome sequence, and target capture sequencing rigorously excluded the possibility of ATLL. Various histological subtypes, such as six nodal T follicular helper cell lymphomas, angioimmunoblastic type/not otherwise specified (nTFHL-AI/NOS), two monomorphic epitheliotropic intestinal T-cell lymphomas (MEITL), two peripheral T-cell lymphomas, NOS (PTCL, NOS), and two anaplastic large cell lymphomas (ALCL), ALK-negative, were included. Each case exhibited immunophenotypes and genetic profiles consistent with its respective histological subtype, but atypical for ATLL. Three nTFHL-AI cases exhibited co-mutations of RHOA p.G17V, TET2, and IDH2 p.R172, characteristic of nTFHL-AI but not of ATLL. Among the molecular analytic modalities included in this study, the combination of HBZ-ISH and HTLV-1-qPCR represented the results obtained from the other more expensive modalities, indicating that this combination is effective in daily practice. When T-cell neoplasms arise in HTLV-1 carriers and exhibit atypical clinical, phenotypical, or genetic features for ATLL, it is recommended to perform HBZ-ISH and HTLV-1-qPCR to distinguish non-ATLL TCLs.

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• Genomic Features of Cervical Cancer in Okinawa, Japan: Preliminary Findings From 23 Patients

  Maemoto Hitoshi, Sakihama Shugo, Karube Kennosuke, Kudaka Wataru, Nakamoto Tomoko, Taira Yusuke, Arakaki Yoshihisa, Shimoji Yuko, Nishie Akihiro

  Cancer Genomics & Proteomics ( International Institute of Anticancer Research )  22 ( 6 ) 1069 - 1080   2025年11月 [ 査読有り ]

  掲載種別: 研究論文（学術雑誌）

  　概要を見る

  Background/Aim: Regional differences in genomic mutation profiles of uterine cervical cancer have been reported. Japanese people are divided into two genetic background clusters, originating from mainland Japan and Okinawa. Okinawa is an island prefecture surrounded by the sea, located more than 800 km from the southernmost point of mainland Japan. No studies have examined gene mutation profiles of cervical cancer in Okinawa. This study aimed to investigate the mutation profile of cervical cancer in Okinawa. Patients and Methods: Twenty‑three patients with biopsy‑proven squamous cell carcinoma and adenocarcinoma of the intact uterine cervix who were treated with definitive radiotherapy were analyzed. Genomic DNA was extracted from fresh frozen tissue samples collected by tumor biopsy prior to treatment. Variants of 224 cancer‑related genes were identified using next‑generation sequencing. Results: A total of 29 gene mutations were observed in 16 patients, including nine genes mutated in multiple samples: SCN7A (17%), PIK3CA (13%), FGFR4 (13%), USP6 (13%), SETD2 (9%), KIT (9%), TSC1 (9%), SERPING1 (9%), and NOTCH3 (9%). Compared to a report from mainland Japan, significant differences in mutation frequency were observed in PIK3CA, FBXW7, and ARID1A. Significant mutations in ARID1A, FBXW7, PTEN, TP53, and EP300, reported as relatively common in cervical cancer in other regions were not detected in this study. The rate of 2‑year overall survival and progression‑free survival was 95.5% and 73.4%, respectively. Conclusion: Gene mutation profiles of cervical cancer in Okinawa may differ from those in other regions.

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• Coactivation of innate immune suppressive cells induces acquired resistance against combined TLR agonism and PD-1 blockade

  Nishinakamura, H; Shinya, S; Irie, T; Sakihama, S; Naito, T; Watanabe, K; Sugiyama, D; Tamiya, M; Yoshida, T; Hase, T; Yoshida, T; Karube, K; Koyama, S; Nishikawa, H

  SCIENCE TRANSLATIONAL MEDICINE ( Science Translational Medicine )  17 ( 785 ) eadk3160   2025年02月 [ 査読有り ]

  掲載種別: 研究論文（学術雑誌）

  　概要を見る

  Immune checkpoint blockade therapy has been successfully applied in clinical settings as a standard therapy for many cancer types, but its clinical efficacy is restricted to patients with immunologically hot tumors. Various strategies to modify the tumor microenvironment (TME), such as Toll-like receptor (TLR) agonists that can stimulate innate immunity, have been explored but have not been successful. Here, we show a mechanism of acquired resistance to combination treatment consisting of an agonist for multiple TLRs, OK-432 (Picibanil), and programmed cell death protein 1 (PD-1) blockade. Adding the TLR agonist failed to convert the TME from immunogenically cold to hot and did not augment antitumor immunity, particularly CD8+ T cell responses, in multiple animal models. The failure was attributed to the coactivation of innate suppressive cells, such as polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) expressing CXCR2, through high CXCL1 production by macrophages in the TME upon OK-432 treatment. A triple combination treatment with OK-432, PD-1 blockade, and a CXCR2 neutralizing antibody overcame the resistance induced by PMN-MDSCs, resulting in a stronger antitumor effect than that of any dual combinations or single treatments. The accumulation of PMN-MDSCs was similarly observed in the pleural effusions of patients with lung cancer after OK-432 administration. We propose that successful combination cancer immunotherapy intended to stimulate innate antitumor immunity requires modulation of unwanted activation of innate immune suppressive cells, including PMN-MDSCs.

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• Recent progress in pathological understanding of adult T-cell leukemia/ lymphoma in the new classification era

  Karube, K; Sakihama, S; Takatori, M; Morichika, K; Tamaki, T; Wada, N; Fukushima, T

  LEUKEMIA RESEARCH ( Leukemia Research )  148   107634 - 107634   2025年01月 [ 査読有り ]

  掲載種別: 研究論文（学術雑誌）

  　概要を見る

  Adult T-cell leukemia/lymphoma (ATLL) is a peripheral T-cell lymphoma caused by Human T-cell leukemia virus type 1 (HTLV-1) infection. Although the 5th Edition of the WHO classification (WHO-5) did not make drastic changes regarding the disease concept of ATLL from the revised 4th Edition of the WHO classification (WHO-4R), WHO-5 newly introduced the essential and desirable diagnostic criteria, namely, "neoplastic lymphoid cell proliferation with mature T-cell phenotype; proven HTLV-1 carriership" and "identification of monoclonal integration of HTLV-1", respectively. To satisfy the desirable criteria, a new diagnostic method using a combination of HBZ-ISH and tax-PCR was introduced for the identification of the HTLV-1 in addition to the conventionally used Southern blot hybridization, especially in the case when only FFPE specimens are available. Morphologically, pleomorphic- and anaplastic large cell-type, account for most cases, while minor variants, ATLL with dermatopathic reaction, angioimmunoblastic T-cell lymphoma-like variant, and classic Hodgkin lymphoma-like variant, should also be noted as diagnostic pitfalls. Phenotypically, about 80 % of ATLL cases show a typical phenotype of CD3 + CD4 +CD25 +CCR4 + , while about 10 % show atypical phenotypes such as T follicular helper cell-like one. Many genetic abnormalities, mainly associated with the TCR signaling pathway, are observed, and most are more frequent in the aggressive type than in the indolent type, except for STAT3, indicating the heterogeneous pathogenic process of ATLL. In this review, we present the latest findings on molecular pathogenesis and histopathological findings of ATLL in the era of the new classification of lymphomas, serving as a basis for future research and classification.

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• <i>Aurantiochytrium</i>抽出液による酸化ストレス誘導性皮膚細胞障害の保護作用

  今泉 直樹, 豊川 洋一, 喜久川 彩佳, 幸喜 拓哉, 崎浜 秀悟, 福島 卓也, 佐々木 努

  日本毒性学会学術年会  2025年  -  2025年   

  CiNii Research

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• 第61回日本リンパ網内系学会総会優秀演題賞

  2021年06月   日本リンパ網内系学会   沖縄県における成人T細胞白血病・リンパ腫における遺伝子異常: HTLV-1-tax遺伝子型に注目した解析  

  受賞者: ■■■

• 平成30年度 若手研究者奨励賞

  2018年09月   日本HTLV-1学会  

  受賞者: 崎浜 秀悟, 森近 一穂, 齋藤 るみ子, 坂井 和子, 西尾 和人, 益崎 裕章, 福島 卓也, 加留部 謙之輔

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• ATLLにおけるPRKCB・CARD11変異共存の臨床的／機能的意義

  若手研究

  課題番号: 2 3 K 1 5 3 0 4

  研究期間: 2023年04月  -  継続中 

• ATLLにおけるPRKCB・CARD11変異共存の臨床的／機能的意義

  若手研究

  課題番号: 23K15304

  研究期間: 2023年04月  -  2025年03月 

  代表者: 崎浜 秀悟 

  直接経費: 3,500,000（円）  間接経費: 4,550,000（円）  金額合計: 1,050,000（円）

  　概要を見る

  ATLは、HTLV-1キャリアの一部が発症する末梢性T細胞悪性腫瘍である。ATL細胞における遺伝子変異はT cell receptor/nuclear factor-κB (NF-κB) 経路関連分子に集積している。特に、PRKCBおよびCARD11の変異は高頻度に検出され、同一症例に併発することが多く、腫瘍細胞の発生・進展に寄与していることが強く疑われる。そこで本研究では、PRKCBおよびCARD11における変異がタンパク質機能および臨床病態に及ぼす影響を解析している。 先行研究におけるコホートを用いた予備解析では、PRKCB変異はCARD11 Coiled-coilドメインの変異と有意に共存していたが、抑制性ドメインの変異とは関連が見られなかった。そこで、再現性を確認するために新たにaggressive ATLの症例を蓄積し、ターゲットシーケンスおよびlong-PCRによる両遺伝子の変異について解析中である。現在のところ50例のサンプルに対する遺伝子変異の検出が完了している。 両遺伝子における変異がタンパク質機能に及ぼす影響を解析するために、ATLにおいて高頻度に報告されているPKCβ変異体1種 (p.D427N) 、およびCARD11変異体4種 (p.D230N, p.D401N, p.S585_R467del, p.F902C) の発現ベクターを作製し、細胞株を用いた検討を進めている。予備実験で実施したHEK293T細胞株を用いたルシフェラーゼアッセイで、相加的にNF-κBを活性化させた両変異の組み合わせについて、ATL細胞株を含むリンパ球系の細胞株で再現性を確認中である。また、両遺伝子の変異の組み合わせにより、CARD11に動員されるタンパク質に違いがあるか検討中である。

• 沖縄県における成人T細胞白血病／リンパ腫のゲノム解析

  若手研究

  課題番号: 19K17835

  研究期間: 2019年04月  -  2021年03月 

  代表者: 崎浜 秀悟 

  直接経費: 3,300,000（円）  間接経費: 990,000（円）  金額合計: 4,290,000（円）