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Faculty of Medicine School of Medicine Department of Internal Medicine, Hematology, Diabetes, and Endocrinology |
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SHIMODA Kazuya
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Degree 【 display / non-display 】
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博士（医学） ( 1994.5 九州大学 )
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医学士 ( 1987.3 九州大学 )
Research Areas 【 display / non-display 】
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Life Science / Hematology and medical oncology
Papers 【 display / non-display 】
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Ichikawa T., Nakahata S., Shimoda K., Murakami T., Morishita K.
Journal of Biological Chemistry 302 ( 6 ) 113080 2026.6
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Biological Chemistry
Adult T-cell leukemia/lymphoma (ATL) is an aggressive T-cell malignancy with a poor prognosis that is caused by human T-cell leukemia virus type 1 infection. We previously demonstrated that N-myc downstream-regulated gene 2 (NDRG2) is significantly downregulated in ATL, resulting in aberrant activation of the signal transduction pathways through the dissociation of serine/threonine protein phosphatase 2A. To identify potential targets of NDRG2, we performed comprehensive mass spectrometry of differentially phosphorylated peptides in ATL cells with overexpression of NDRG2 using a TiO<inf>2</inf>-based enrichment method. Kyoto Encyclopedia of Genes and Genomes and gene ontology analysis revealed that the downregulated phosphopeptides correlated with signaling pathways, T-cell differentiation, and proliferation. Our results identified signal transducer and activator of transcription 5B as a novel NDRG2-regulated protein that is dephosphorylated at serine 193 and tyrosine 699. Although enforced expression of NDRG2 in ATL cell lines does not change the phosphorylation of Janus kinase 3, an upstream regulator of STAT5, phosphorylated STAT5 at tyrosine and serine is significantly suppressed by the direct binding to STAT5 with NDRG2 leading to the inhibition of STAT5 downstream gene expression. Furthermore, NDRG2 binds to STAT5B with alanine replacement of Y699 (Y699A), but only weakly associates with S193A, suggesting that NDRG2 is directly involved in serine phosphorylation through the recruitment of serine/threonine protein phosphatase 2A to STAT5. Because S193 A remarkably induces reduced phosphorylation of Y699 and subsequent transcriptional activity, the induction of serine phosphorylation through the loss of NDRG2 expression is dispensable for STAT5 tyrosine phosphorylation and activity. Since the loss of NDRG2 expression is essential factor to maintenance of ATL cells by STAT5 activity through phosphorylation of serine and tyrosine, targeting STAT5 becomes a feasible and effective strategy in NDRG2-deficient ATL.
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Gi T., Kai K., Shide K., Nakamura E., Oguri N., Aman M., Maekawa K., Moriguchi-Goto S., Nakai M., Shimoda K., Hisada Y., Yamashita A.
Research and Practice in Thrombosis and Haemostasis 10 ( 3 ) 103433 2026.3
Language：English Publishing type：Research paper (scientific journal) Publisher：Research and Practice in Thrombosis and Haemostasis
Background: Intracranial hemorrhage (ICH) is a fatal complication of leukemia; however, mechanisms underlying its development, particularly central nervous system (CNS) involvement and vascular injury, remain unclear. Objectives: We aimed to investigate the histopathologic features of cerebral vessels in leukemia and the expression of hemostasis-related factors in leukemia cells. Methods: We conducted an autopsy-based study including 37 leukemia cases and 20 matched controls. Histopathologic analysis of CNS tissues was performed to evaluate ICH, leukemia cell localization, and vascular injury. Immunohistochemistry was performed to assess expression of vascular endothelial growth factor (VEGF), cathepsin G, tissue-type plasminogen activator, urokinase-type plasminogen activator, urokinase-type plasminogen activator receptor, and tissue factor in leukemia cells. Vascular integrity was evaluated using stains for smooth muscle actin, collagen, fibrin, and von Willebrand factor. Results: ICH was identified in 68% of leukemia cases and was associated with fatal brain herniation in 40%. CNS involvement was observed in 54% of cases, often without a clinical diagnosis. The leukemia cell infiltration of meninges and vascular walls was frequently associated with changes in smooth muscle cells and adventitial collagen. CNS vascular injury was frequently associated with ICH in the presence of leukemia cell infiltration. VEGF and urokinase-type plasminogen activator were highly expressed in leukemia cells. VEGF was associated with meningeal invasion, while cathepsin G was predominantly expressed in myeloid leukemia and linked to vascular damage. Conclusion: VEGF and cathepsin G may serve as markers of meningeal invasion and cerebral vascular damage in leukemia, respectively.
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Ichikawa T., Shimosaki S., Nakahata S., Suekane A., Kitabayashi I., Iha H., Shimoda K., Murakami T., Morishita K.
Cancer Gene Therapy 33 ( 3 ) 314 - 322 2026.3
Language：English Publishing type：Research paper (scientific journal) Publisher：Cancer Gene Therapy
Inactivation of PTEN by post-translational modifications causes aberrant amplification of the PI3K/AKT signaling pathway in many tumors. PTEN is a tumor suppressor phosphatase that is frequently phosphorylated at conserved serine/threonine residues (S380, T382, and T383 clusters) in the C-terminal tail of ATL and various solid cancer cells. Here, we identify SCY1-like protein 2 (SCYL2), with a protein kinase-like domain, as a novel PTEN-binding protein; however, the mechanism by which SCYL2 regulates PTEN phosphorylation remains unclear. SCYL2-associated complex phosphorylates PTEN at STT, and SCYL2 downregulation has anti-tumor effects in ATL via inhibition of the PI3K/AKT signaling pathway by dephosphorylating PTEN at STT. SCYL2 reportedly binds to the clathrin heavy chain (CHC), which regulates cytoplasmic vesicle formation, trafficking, and signaling pathways. Our results indicate that SCYL2 expression induces the binding of CHC to PTEN. Furthermore, the inhibition of clathrin-coated vesicles (CCVs) by CHC downregulation or inhibition suppresses cell survival by reducing phosphorylated PTEN at the STT, suggesting that SCYL2 enhances PTEN phosphorylation through CCVs as a signaling platform. Our results indicate that SCYL2/CHC complex plays a pivotal role in regulating the PI3K/AKT signaling pathway through PTEN phosphorylation, thus leading to tumor development and may be a promising novel target for treating tumors.
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Tahira Y., Shide K., Kameda T., Uchida T., Kamiunten A., Akizuki K., Kubuki Y., Karasawa M., Ikeda R., Matsumoto K., Bai J., Terashima M., Kato K., Uto T., Fukaya T., Mitoma S., Sato K., Uehira Y., Ueno H., Sashida G., Yamaguchi H., Shimoda K.
Blood Neoplasia 2 ( 3 ) 100087 2026.1
Language：English Publishing type：Research paper (scientific journal) Publisher：Blood Neoplasia
Interferon-α (IFN-α) exhibits antiviral and antiproliferative effects on normal and neoplastic cells. Intracellular signaling of IFN-α is mediated by tyrosine kinase 2 (TYK2) and janus kinase 1 (JAK1), followed by signal transducers and activators of transcription (STATs). TYK2 is redundant for the antiviral effect of IFN-α; however, the requirements for antiproliferative effects are unknown. We assessed the role of TYK2 in the effects of IFN-α in myeloproliferative neoplasm (MPN) model mice. Jak2V617F transgenic mice develop MPNs resembling human primary myelofibrosis, and ropeginterferon-α-2b ameliorated their features. However, these IFN-α effects were absent in Jak2V617F;Tyk2<sup>−/−</sup> mice. In mixed wild-type (WT)/Jak2V617F chimeric mice, IFN-α treatment induces Jak2V617F hematopoietic stem cells (HSCs) to enter the cell cycle and skew their differentiation into the megakaryocyte lineage, decreasing the number of Jak2V617F HSCs. The effects of IFN-α on Jak2V617F HSCs were not observed in mixed WT/Jak2V617F;Tyk2<sup>−/−</sup> mice, indicating that TYK2 is essential for the effects of IFN-α on both Jak2V617F progenitors and HSCs. The mechanism of IFN-α in Jak2V617F HSCs and progenitors differed: genes regulating the cell cycle were enriched in IFN-α–stimulated Jak2V617F HSCs, but not in Jak2V617F progenitors; genes regulating antiproliferation were enriched in IFN-α–stimulated Jak2V617F progenitors but not in Jak2V617F HSCs. The major IFN-α signaling molecule activated by JAKs is STAT1, which is essential for the antiviral effect. Most effects of IFN-α on Jak2V617F cells were preserved in Jak2V617F;Stat1<sup>−/−</sup> mice but to a moderate degree compared with Jak2V617F mice. Our study reveals essential roles of TYK2 for the preferential suppressive effect of IFN-α on Jak2V617F progenitors and HSCs.
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Shimazu Y., Kameda T., Kitawaki T., Kamiunten A., Sekine M., Kawano H., Sato S., Maeda K., Toyama T., Kawano N., Yamashita K., Takeuchi M., Ishizaki J., Shimoda K., Takaori-Kondo A.
Clinical Immunology 282 110616 2026.1
Language：English Publishing type：Research paper (scientific journal) Publisher：Clinical Immunology
Background: Mogamulizumab, an anti-CCR4 monoclonal antibody, is approved for relapsed/refractory (r/r) aggressive adult T-cell leukemia/lymphoma (ATL), although durable responses are limited. Objective: To identify biomarkers associated with mogamulizumab efficacy, focusing on host immune status and known prognostic factors. Methods: We retrospectively analyzed 315 patients with r/r aggressive ATL using real-world data from Japan. Clinical and prognostic variables were analyzed for association with overall survival (OS), stratified by mogamulizumab use. Results: Among 315 patients, 97 received mogamulizumab (Moga [+]). One-year OS was higher in Moga (+) than Moga (−) patients (51.2 % vs. 34.0 %, p = 0.006). Multivariate analysis identified age < 70, PS 0–1, cCa < 11 mg/dL, albumin ≥3.5 g/dL, LDH < 265 IU/L, LMR ≥ 2.6, and Moga (+) use as independent predictors of OS. In Moga (+) patients, cCa and LMR remained independent prognostic factors. Conclusion: LMR is a novel prognostic factor in r/r ATL and may provide useful information when considering mogamulizumab-based treatment.
Books 【 display / non-display 】
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イヤーノート2026 内科・外科編
下田和哉 他（ Role： Joint author , 血液学総論（造血幹細胞移植~脾摘術）、白血球系の異常(白血球増加症～骨髄異形成症候群)、白血球系の異常（悪性リンパ腫以外の成熟B細胞腫瘍～成熟T細胞腫瘍））
株式会社メディックメディア 2025.3
Book type：Scholarly book
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WHO分類第5版による白血病・リンパ系腫瘍の病態学
久冨木庸子、下田和哉 他（ Role： Contributor , 骨髄性／リンパ性腫瘍）
中外医学社 2024.12
Book type：Scholarly book
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イヤーノート2025 内科・外科編
下田和哉 他（ Role： Joint author , 血液学総論（造血幹細胞移植~脾摘術）、白血球系の異常(白血球増加症～骨髄異形成症候群)、白血球系の異常（悪性リンパ腫以外の成熟B細胞腫瘍～成熟T細胞腫瘍））
株式会社メディックメディア 2024.3
Book type：Scholarly book
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別冊日本臨牀 血液症候群（第3版）ーその他の血液疾患を含めてーⅣ
亀田拓郎、幣光太郎、下田和哉（ Role： Joint author , 本態性血小板血症）
株式会社 日本臨牀社 2024.2
Responsible for pages：27-32頁 Language：Japanese Book type：Scholarly book
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血液専門医テキスト(改訂第4版)
下田和哉 他（ Role： Joint author , その他の骨髄増殖性疾患 252-254頁）
株式会社 南江堂 2023.10
Language：Japanese Book type：Textbook, survey, introduction
MISC 【 display / non-display 】
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診療ガイドラインat a glance 造血器腫瘍診療ガイドライン第3.1版(2024年改訂版)
尾崎 修治、下田 和哉、 日本血液学会造血器腫瘍診療ガイドライン委員会
日本内科学会雑誌 114 ( 12 ) 2278 - 2284 2025.12
Publishing type：Rapid communication, short report, research note, etc. (scientific journal) Publisher：(一社)日本内科学会
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RINKETSU Dictionary 骨髄線維症に対する新規JAK阻害薬momelotinib
下田和哉
臨床血液 66 ( 7 ) 727 2025.7
Publishing type：Rapid communication, short report, research note, etc. (scientific journal)
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第5土曜特集 マルチオミクスが解き明かす疾患の本質--統合的アプローチによる新たな知見 疾患別マルチオミクス解析の最新動向 【がん】 マルチオミクス解析による血液がんの病態解明と臨床への展開
亀田 拓郎, 下田 和哉
医学のあゆみ 293 ( 9 ) 804 - 810 2025.5
Publishing type：Rapid communication, short report, research note, etc. (scientific journal) Publisher：医歯薬出版
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骨髄線維症に対するruxolitinibとmomelotinibの有効性と位置づけ
幣光太郎、下田和哉
血液内科 90 ( 5 ) 553 - 559 2025.5
Publishing type：Rapid communication, short report, research note, etc. (scientific journal)
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【新・白血病学(上)-病態・診断・診療-】白血病の発症と病態形成 白血病の染色体異常・遺伝子異常と病態形成機構 各論 骨髄増殖性腫瘍の分子病態
長嶺宏士朗、下田和哉
日本臨床 83 ( 増刊4 ) 2025.4
Publishing type：Rapid communication, short report, research note, etc. (scientific journal)
Presentations 【 display / non-display 】
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ATL新規治療標的同定と、個別化医療への展開
下田和哉
令和7年度AMED革新がん領域1全体会議 (東京都) 2025.7.26 日本医療研究開発機構研究費 （革新的がん医療実用化研究）
Event date： 2025.7.26
Presentation type：Oral presentation (general)
Venue：東京都
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後期高齢者に対するSGLT2阻害薬の使用実態と安全性についての多施設共同後方視的コホート研究
内田泰介、上野浩晶、小永田綾香、中村孝之、古郷芙未子、鍋倉弘樹、田中友梨、上平雄大、山口秀樹、下田和哉：
第67回日本老年医学会学術集会 (千葉市) 2025.6.27 杏林大学医学部高齢医学教室
Event date： 2025.6.27 - 2025.6.29
Presentation type：Poster presentation
Venue：千葉市
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BRAFV600E変異陽性甲状腺乳頭癌の加療中に発生したBRAFV600E変異陰性甲状腺未分化癌の1剖検例
内田泰介、山口秀樹、菊池幸、別府拓海、積島愛加理、積島宏昂、古郷芙未子、鍋倉弘樹、与那嶺真一、上平雄大、上野浩晶、田中智章、盛口清香、山下篤、下田和哉：
第98回日本内分泌学会学術総会 (千葉市) 2025.6.6 千葉大学大学院医学研究院 内分泌代謝・血液・老年内科学
Event date： 2025.6.5 - 2025.6.7
Presentation type：Oral presentation (general)
Venue：千葉市 Country：Japan
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放射性ヨウ素内用療法後に甲状腺中毒症が遷延したバセドウ病の1例
別府拓海、鍋倉弘樹、内田泰介、菊池幸、古郷芙未子、積島愛加理、与那嶺真一、上平雄大、上野浩晶、寺田珠沙、東美菜子、山口秀樹、下田和哉：
第98回日本内分泌学会学術総会 (千葉市) 2025.6.5 千葉大学大学院医学研究院 内分泌代謝・血液・老年内科学
Event date： 2025.6.5 - 2025.6.7
Presentation type：Poster presentation
Venue：千葉市
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腹部外科術後のショックバイタルを契機に発見された医原性副腎不全の1例
菊池幸、古郷芙未子、別府拓海、積島愛加理、鍋倉弘樹、内田泰介、与那嶺真一、上平雄大、上野浩晶、山口秀樹、下田和哉：
第98回日本内分泌学会学術総会 (千葉市) 2025.6.5 千葉大学大学院医学研究院 内分泌代謝・血液・老年内科学
Event date： 2025.6.5 - 2025.6.7
Presentation type：Poster presentation
Venue：千葉市
Awards 【 display / non-display 】
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日本白血病研究基金 清水賞
2002.11 日本白血病研究基金
下田和哉
Award type：Award from publisher, newspaper, foundation, etc. Country：Japan
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日本癌学会奨励賞
2002.10 日本がん学会
下田和哉
Award type：Award from Japanese society, conference, symposium, etc. Country：Japan
Grant-in-Aid for Scientific Research 【 display / non-display 】
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新規病態：HTLV-1陽性HRS細胞を伴う成人T細胞白血病/リンパ腫の統合的解析
Grant number：23K27384 2023.04 - 2027.03
独立行政法人日本学術振興会 科学研究費基金 基盤研究(B)
Authorship：Coinvestigator(s)
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新規病態：HTLV-1陽性HRS細胞を伴う成人T細胞白血病/リンパ腫の統合的解析
Grant number：23H02693 2023.04 - 2027.03
独立行政法人日本学術振興会 科学研究費補助金 基盤研究(B)
Authorship：Coinvestigator(s)
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腫瘍性fibrocyteの本態解明と、骨髄線維症診断・治療への展開
Grant number：23K27629 2023.04 - 2026.03
独立行政法人日本学術振興会 科学研究費基金 基盤研究(B)
Authorship：Principal investigator
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腫瘍性fibrocyteの本態解明と、骨髄線維症診断・治療への展開
Grant number：23H02938 2023.04 - 2026.03
独立行政法人日本学術振興会 科学研究費補助金 基盤研究(B)
Authorship：Principal investigator
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1007創薬に向けた、CALR変異とfibrocyteに着目する骨髄増殖性腫瘍研究
Grant number：17H04210 2017.04 - 2019.03
科学研究費補助金 基盤研究(B)
下田和哉、久冨木庸子、日髙智徳、幣光太郎
Authorship：Principal investigator
骨髄増殖性腫瘍(MPN)のドライバー変異であるJAK2,CALR変異が同定されMPNの病態が明らかにされつつあるが、CALR変異がMPNを発症させる機序や、骨髄線維症の本態である骨髄線維化細胞の起源、つまり間質の反応性変化なのか、あるいは腫瘍クローン由来fibrocyteなのかは不明である。本研究では以下の3つの方法により、MPNの新たな治療につながる研究を行う。
Ⅰ. MPLとの会合やSTAT活性化に必須な変異CALRの領域同定と、その阻害による治療開発
Ⅱ. 本態性血小板血症から骨髄線維症へ進展する分子イベントの同定
Ⅲ. 腫瘍クローン由来fibrocyteが骨髄線維化に果たす役割の同定と、骨髄線維化を改善することをすでに見出しているMEK阻害剤がfibrocyteに及ぼす影響の解明
Past consigned research fund received 【 display / non-display 】
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A Phase 2b Open-Label Single-Arm Study to Evaluate the Efficacy and Safety of Oral HBI-8000 in Patients with Relapsed or Refractory Adult T Cell Lymphoma(ATL)
2017.01 - 2019.12
Investigational New Drug Test
Consigned research type：Investigational New Drug Test
Available Technology 【 display / non-display 】
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骨髄増殖性腫瘍、病因遺伝子の機能解析と新規治療法開発
白血病細胞のゲノム情報に基づく成人T細胞白血病の克服戦略Home Page： 内科学講座 血液・糖尿病・内分泌学分野
Related fields where technical consultation is available：・血液疾患マウスモデルの作成と解析、治療法開発への応用
・サイトカインシグナル伝達機構の解析
（共同研究が可能なテーマ）骨髄増殖性腫瘍、成人T細胞白血病を対象とした研究