Can allelic polymorphisms of KIRs predict TFR in CML?

• Project/Area Number: 19K17860
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Saga University
• Principal Investigator: Ureshino Hiroshi 佐賀大学, 医学部, 病院講師 (00807464)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 慢性骨髄性白血病 / NK細胞免疫 / KIR遺伝子多型 / T細胞免疫 / HLA多型 / 無治療寛解維持 / KIR / HLA / TKI / KIRアリル多型 / Treatment free remission

Outline of Research at the Start

慢性骨髄性白血病(chronic myeloid leukemia; CML)のチロシンキナーゼ阻害剤中止後におけるtreatment-free remissionの維持にNK細胞免疫が関わる。NK細胞には Killer immunoglobulin-like receptor (KIR)を介したNK細胞活性制御機構があり、次世代シークエンサー(NSG)によるKIRのアリル多型解析の結果、KIR3DL1*005を有する個体でNK細胞免疫を介したCMLの治療効果が高いことを我々は見出した。この結果に基づき我々は、KIR のアリル多型がCMLにおけるTFRに影響を及ぼすかを検証する。

Outline of Final Research Achievements

We investigated the association between KIR/HLA polymorphisms in patients with chronic myeloid leukemia(CML). HLA allelic polymorphisms was associated with the achievement of treatment free remission (TFR) after tyrosine kinase inhibitor (TKI) discontinuation. Patients who could discontinue TKI had higher NK cell activation status compared with patients who could not. Meanwhile, NK cell activation status did not affect the achievement of TFR in patients with CML. These results suggest NK cell activation can be associated with the achievement of DMR during TKI treatment, while T-cell activation can be associated with the achievement of TFR after TKI discontinuation in patients with CML.

Academic Significance and Societal Importance of the Research Achievements

慢性骨髄性白血病の治療経過におけるNK細胞及びT細胞免疫の役割分担の可能性について示すことができた。NK細胞やT細胞免疫活性化を起こさせる何らかのチロシンキナーゼ阻害剤（TKI)との併用療法を考案することで、より多くの人がTKI中止を行うことができ、それに引き続くTKI中止後の寛解維持を行うことができると考える。より多くの人が無治療寛解維持を達成することで医療費の削減に寄与できると考える。

Research Products

• [Journal Article] Treatment-free remission and immunity in chronic myeloid leukemia (2021)
  • Author(s): Ureshino Hiroshi
  • Journal Title: International Journal of Hematology Volume: in press Issue: 5 Pages: 642-647
  • DOI: 10.1007/s12185-021-03117-7
• [Journal Article] Dasatinib-Blinatumomab for Ph-Positive ALL (2021)
  • Author(s): Kazuharu Kamachi, Hiroshi Ureshino
  • Journal Title: N Engl J Med. Volume: 384 Issue: 4 Pages: 384-384
  • DOI: 10.1056/nejmc2033785
• [Journal Article] HLA Polymorphisms Are Associated with Treatment-Free Remission Following Discontinuation of Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia (2021)
  • Author(s): Ureshino H, Shindo T, Tanaka H, Saji H, Kimura S
  • Journal Title: Molecular Cancer Therapeutics Volume: 20 Issue: 1 Pages: 142-149
  • DOI: 10.1158/1535-7163.mct-20-0336
  • Peer Reviewed / Open Access
• [Journal Article] A methotrexate-associated lymphoproliferative disorder expressing CD10 and BCL6 with the IGH/CCND1 translocation (2020)
  • Author(s): Katsuya Hiroo、Kizuka-Sano Haruna、Yokoo Masako、Kidoguchi Keisuke、Yamaguchi Kyosuke、Nishioka Atsujiro、Ureshino Hiroshi、Kubota Yasushi、Ando Toshihiko、Naito Shinji、Ohshima Koichi、Kimura Shinya
  • Journal Title: Annals of Hematology Volume: 99 Issue: 10 Pages: 2449-2451
  • DOI: 10.1007/s00277-020-04218-9
• [Journal Article] Surrogate Markers for Treatment-Free Remission in Patients With Chronic Myeloid Leukemia (2020)
  • Author(s): Ureshino Hiroshi、Kamachi Kazuharu、Kimura Shinya
  • Journal Title: Clinical Lymphoma Myeloma and Leukemia Volume: 20 Issue: 12 Pages: 785-790
  • DOI: 10.1016/j.clml.2020.07.004
• [Journal Article] Allelic polymorphisms of KIRs and antitumor immunity against chronic myeloid leukemia (2020)
  • Author(s): Shindo Takero、Ureshino Hiroshi、Kojima Hiroto、Tanaka Hidenori、Kimura Shinya
  • Journal Title: Immunological Medicine Volume: in press Issue: 2 Pages: 1-8
  • DOI: 10.1080/25785826.2020.1796062
  • Peer Reviewed / Open Access
• [Journal Article] J-SKI will be able to elucidate whether the renal function recover or not after discontinuation of tyrosine kinase inhibitors (2020)
  • Author(s): Okamoto Sho、Ureshino Hiroshi、Kimura Shinya
  • Journal Title: International Journal of Hematology Volume: 112 Issue: 3 Pages: 429-430
  • DOI: 10.1007/s12185-020-02945-3
• [Journal Article] Vascular events may predict the prognosis of patients with chronic myeloid leukemia (2020)
  • Author(s): Ureshino Hiroshi、Kamachi Kazuharu
  • Journal Title: International Journal of Hematology Volume: 112 Issue: 2 Pages: 263-263
  • DOI: 10.1007/s12185-020-02889-8
• [Journal Article] Targeting aberrant DNA hypermethylation as a driver of ATL leukemogenesis by using the new oral demethylating agent OR-2100 (2020)
  • Author(s): Watanabe Tatsuro、Yamashita Satoshi、Ureshino Hiroshi、Kamachi Kazuharu、Kurahashi Yuki、Fukuda-Kurahashi Yuki、Yoshida Nao、Hattori Naoko、Nakamura Hideaki、Sato Akemi、Kawaguchi Atsushi、Sueoka-Aragane Naoko、Kojima Kensuke、Okada Seiji、Ushijima Toshikazu、Kimura Shinya、Sueoka Eisaburo
  • Journal Title: Blood Volume: 136 Issue: 7 Pages: 871-884
  • DOI: 10.1182/blood.2019003084
  • Peer Reviewed / Open Access
• [Journal Article] Assessment of estimated glomerular filtration rate in patients with chronic myeloid leukemia following discontinuation of tyrosine kinase inhibitors (2020)
  • Author(s): Okamoto Sho、Ureshino Hiroshi、Kawaguchi Atsushi、Miyazono Motoaki、Ikeda Yuji、Kimura Shinya
  • Journal Title: International Journal of Hematology Volume: 112 Issue: 1 Pages: 41-45
  • DOI: 10.1007/s12185-020-02880-3
• [Journal Article] Does Patient Sex Play a Role in Treatment-Free Remission in Chronic Myeloid Leukemia? (2020)
  • Author(s): Ureshino H, Kamachi K, Kimura S
  • Journal Title: International journal of Hematology Volume: in press Issue: 6 Pages: 903-903
  • DOI: 10.1007/s12185-020-02864-3
  • Peer Reviewed
• [Journal Article] Immune Dysregulation Syndrome With De Novo CTLA4 Germline Mutation Responsive to Abatacept Therapy (2020)
  • Author(s): Ureshino H, Koarada S, Kamachi K, Yoshimura M, Yokoo M, Kubota Y, Ando T, Ichinohe T, Morio T, Kimura S
  • Journal Title: International journal of Hematology Volume: in press Issue: 6 Pages: 897-902
  • DOI: 10.1007/s12185-020-02834-9
  • Peer Reviewed / Open Access
• [Journal Article] Treatment-free remission after first-line dasatinib discontinuation in patients with chronic myeloid leukaemia (first-line DADI trial): a single-arm, multicentre, phase 2 trial (2020)
  • Author(s): Kimura Shinya、Imagawa Jun、Murai Kazunori、Hino Masayuki、Kitawaki Toshio、Okada Masaya、Tanaka Hideo、Shindo Motohiro、Kumagai Takashi、Ikezoe Takayuki、Uoshima Nobuhiko、Sato Tsutomu、Watanabe Reiko、Kowata Shugo、Hayakawa Masaya、Hosoki Takaaki、Ikeda Kazuhiko、et al.
  • Journal Title: The Lancet Haematology Volume: 7 Issue: 3 Pages: 218-225
  • DOI: 10.1016/s2352-3026(19)30235-2
  • Peer Reviewed / Open Access
• [Journal Article] Reconstitution of NK Cells Expressing KIR3DL1 Is Associated With Reduced NK Cell Activity and Relapse of CML After Allogeneic Hematopoietic Stem Cell Transplantation (2020)
  • Author(s): Ureshino H, Shindo T, Sano H, Kubota Y, Ando T, Kidoguchi K, Kusaba K, Itamura H, Kojima H, Kusunoki Y, Miyazaki Y, Kojima K, Tanaka H, Saji H, Oshima K, Kimura S
  • Journal Title: International Journal of Hematology Volume: 111 Issue: 5 Pages: 733-738
  • DOI: 10.1007/s12185-019-02809-5
  • Peer Reviewed
• [Journal Article] Clinical impact of the CONUT score in patients with multiple myeloma (2020)
  • Author(s): Okamoto S, Ureshino H*, Kidoguchi K, Kusaba K, Kizuka-Sano H, Sano H, Nishioka A, Yamaguchi K, Kamachi K, Itamura H, Yoshimura M, Yokoo M, Shindo T, Kubota Y, Ando T, Kojima K, Kawaguchi A, Sueoka E, Kimura S.
  • Journal Title: Ann Hematol Volume: 99 Issue: 1 Pages: 113-119
  • DOI: 10.1007/s00277-019-03844-2
  • Peer Reviewed
• [Journal Article] Role of cancer immunology in chronic myelogenous leukemia. (2020)
  • Author(s): Ureshino H, Shindo T, Kimura S
  • Journal Title: Leuk Res Volume: 88 Pages: 196273-196273
  • DOI: 10.1016/j.leukres.2019.106273
  • Peer Reviewed
• [Journal Article] Mogamulizumab for the Treatment of Adult T-cell Leukemia/Lymphoma (2019)
  • Author(s): Ureshino Hiroshi、Kamachi Kazuharu、Kimura Shinya
  • Journal Title: Clinical Lymphoma Myeloma and Leukemia Volume: 19 Issue: 6 Pages: 326-331
  • DOI: 10.1016/j.clml.2019.03.004
  • Peer Reviewed
• [Journal Article] Japan's high-cost medical expense benefit system could be an obstacle to promoting generic imatinib (2019)
  • Author(s): Ureshino Hiroshi、Kamachi Kazuharu、Kimura Shinya
  • Journal Title: The Lancet Haematology Volume: 6 Issue: 10 Pages: e498-e498
  • DOI: 10.1016/s2352-3026(19)30168-1
  • Peer Reviewed
• [Presentation] 新規DNAメチル化阻害剤OR2100はCDA耐性を獲得し経口吸収性とMDS/AMLへの抗腫瘍効果を有する (2020)
  • Author(s): 嬉野博志、渡邉達郎、通山薫、岡田誠治、原田浩徳、牛島俊和、木村晋也
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] 成人T細胞性白血病/リンパ腫におけるT細胞受容体シグナル制御分子THEMISのDNAメチル化異常 (2020)
  • Author(s): 渡邉達郎、嬉野博志、山下聡、牛島俊和、岡田誠治、末岡榮三郎、木村晋也
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] 慢性骨髄性白血病に対する新規DNA脱メチル化剤OR2100の効果はp53発現により異なる (2020)
  • Author(s): 蒲池和晴、嬉野博志、倉橋祐樹、吉田奈央、山本雄大、渡邉達郎、木村晋也
  • Organizer: 第24回日本がん分子標的治療学会学術集会
• [Presentation] 新規経口DNA脱メチル化剤OR21はAzacitidine耐性を克服する (2020)
  • Author(s): 嬉野博志、蒲池和晴、吉田奈央、倉橋祐樹、渡邉達郎、木村晋也
  • Organizer: 第24回日本がん分子標的治療学会学術集会
• [Presentation] 成人T細胞性白血病/リンパ腫に対するDNA脱メチル化剤とEZH2阻害剤の併用療法 (2020)
  • Author(s): 倉橋祐樹、渡邉達郎、嬉野博志、蒲池和晴、吉田奈央、山本雄大、木村晋也
  • Organizer: 第24回日本がん分子標的治療学会学術集会
• [Presentation] 成人T細胞性白血病/リンパ腫におけるDNAメチル化異常によるT細胞受容体シグナル制御の破綻 (2020)
  • Author(s): 渡邉達郎、嬉野博志、倉橋祐樹、蒲池和晴、吉田奈央、山本雄大、末岡榮三郎、木村晋也
  • Organizer: 第24回日本がん分子標的治療学会学術集会
• [Presentation] ATLL細胞株におけるDNA脱メチル化剤耐性獲得機序 (2020)
  • Author(s): 吉田奈央、渡邉達郎、嬉野博志、倉橋祐樹、蒲池和晴、山本雄大、末岡榮三郎、木村晋也
  • Organizer: 第24回日本がん分子標的治療学会学術集会
• [Presentation] 慢性骨髄性白血病のTFR成功はHLAの多型により予測できる (2020)
  • Author(s): 嬉野博志、進藤岳郎、木村晋也
  • Organizer: 第82回日本血液学会学術集会
• [Presentation] 新規経口脱メチル化剤 O R-2100はチロシンキナーゼ阻害剤の効果を高める (2020)
  • Author(s): 蒲池和晴、嬉野博志、吉田奈央、山本雄大、倉橋祐樹、渡邊達郎、岡田誠治、木村晋也
  • Organizer: 第82回日本血液学会学術集会
• [Presentation] 末梢血幹細胞移植後に急性骨髄性白血病へと系統変化したBCR-ABL(+)急性リンパ性白血病の1例 (2020)
  • Author(s): 海野晃久、佐野遥菜、安藤寿彦、嬉野博志、吉谷美穂、岡崎智満、吉原由利重、南里安耶、若山一夫、川崎誠司、木村晋也、末岡栄三郎
  • Organizer: 第82回日本血液学会学術集会
• [Presentation] 成人T細胞性白血病／リンパ腫に対するDNA脱メチル化剤とEZH阻害剤の併用効果と標的因子DUSP5 (2020)
  • Author(s): 倉橋祐樹、吉田奈央、嬉野博志、蒲池和晴、山本雄大、渡邊達郎、木村晋也
  • Organizer: 第82回日本血液学会学術集会
• [Presentation] 成人T細胞性白血病／リンパ腫におけるT細胞受容体シグナル制御分子のDNAメチル化異常の細胞生物学的意義 (2020)
  • Author(s): 渡邊達郎、吉田奈央、嬉野博志、蒲池和晴、倉橋祐樹、山本雄大、山下聡、岡田誠治、牛島俊和、末岡栄三郎、木村晋也
  • Organizer: 第82回日本血液学会学術集会
• [Presentation] ATLL細胞株のDNAメチル化阻害剤に対する耐性獲得機序 (2020)
  • Author(s): 吉田奈央、渡邊達郎、倉橋祐樹、嬉野博志、蒲池和晴、山本雄大、木村晋也
  • Organizer: 第82回日本血液学会学術集会
• [Presentation] 当院における濾胞性リンパ腫の治療成績 (2020)
  • Author(s): 長家聡明、勝屋弘雄、安藤れい子、城戸口啓介、佐野遥菜、山口亨祐、蒲池和晴、嬉野博志、久保田寧、安藤寿彦、木村晋也
  • Organizer: 第82回日本血液学会学術集会
• [Presentation] 腎偶発腫瘍で発見され、イブルチニブ単剤治療により1年半安定状態を得ているFCR後再発小リンパ球性リンパ腫 (2020)
  • Author(s): 小島研介、嬉野博志、木村晋也
  • Organizer: 第60回リンパ網内系学会総会
• [Presentation] A NEW HYPOMETHYLATING AGENT, OR-2100, RESISTS DEGRADATION BY CYTIDINE DEAMINASE, LEADING TO FAVOURABLE ORAL ABSORBABILITY AND ANT-LEUKAEMIA EFFECTS (2020)
  • Author(s): Hiroshi Ureshino, Kazuharu Kamachi, Tatsuro Watanabe, Yuki Kurahashi, Kaoru Tohyama, Seiji Okada, Toshikazu Ushijima, Shinya Kimura
  • Organizer: 25th EHA Congress virtual
  • Int'l Joint Research
• [Presentation] HLA POLYMORPHISMS PREDICT TREATMENT-FREE REMISSION FOLLOWING TKI DISCONTINUATION IN PATIENTS WITH CHRONIC MYELOID LEUKEMIA (2020)
  • Author(s): Hiroshi Ureshino, Takero Shindo, Hidenori Tanaka, Hiroo Saji, Shinya Kimura
  • Organizer: 25th EHA Congress virtual
  • Int'l Joint Research
• [Presentation] アバタセプトが奏功したCTLA4ハプロ不全症による免疫異常症 (2020)
  • Author(s): 宮﨑真理子, 嬉野博志, 小荒田秀一, 宮原 正晴, 蒲池和晴, 吉村麻里子, 横尾眞子, 久保田寧, 安藤寿彦, 一戸辰夫, 森尾知宏, 木村晋也
  • Organizer: 第10回日本血液学会九州地方会
• [Presentation] びまん性大細胞型B細胞リンパ腫に合併した続発性膜性腎症の一例 (2020)
  • Author(s): 永田 絢子, 力武 修一, 城戸口 啓介, 橋本 優香, 野中 枝理子, 野中 真衣, 福田 誠, 吉原 万貴, 勝屋 弘雄, 嬉野 博志, 高島 毅, 木村 晋也, 宮園 素明
  • Organizer: 第50回日本腎臓学会東部学術大会
• [Presentation] Efficacy of OR-21, a new oral DNA methyltransferase inhibitor in chronic myeloid leukemia (2019)
  • Author(s): Kazuharu Kamachi，Hiroshi Ureshino，Yuki Kurahashi， Yuki Kurahashi，Tatsuro Watanabe，Seiji Okada，Shinya Kimura
  • Organizer: 第81回日本血液学会学術集会
• [Presentation] Eficacy of DNA demethylating agents and related molecular targets in adult-T cell leukemia-lymphoma (2019)
  • Author(s): Tatsuro Watanabe，Hiroshi Ureshino，Kazuharu Kamachi， Yuki Kurahashi，Yuki Kurahashi，Satoshi Yamashita，Seiji Okada， Toshikazu Ushijima，Eisaburo Sueoka，Shinya Kimura
  • Organizer: 第81回日本血液学会学術集会
• [Presentation] 慢性骨髄性白血病に対するチロシンキナーゼ阻害剤の治療効果は KIR と HLA のアレル多型で予測できる (2019)
  • Author(s): 進藤岳郎、嬉野博志、木村晋也
  • Organizer: 第78回日本癌学会学術集会
• [Presentation] 成人 T 細胞白血病/リンパ腫における DNA メチル化異常の細胞生物学的意義と治療標的としての可能性 (2019)
  • Author(s): 渡邉 達郎、嬉野 博志、山下 聡、牛島 俊和、岡田 誠治、末岡 榮三朗、木村 晋也
  • Organizer: 第78回日本癌学会学術集会
• [Presentation] 新規デシタビンプロドラッグOR21は分化及びがん抑制遺伝子の発現を誘導する (2019)
  • Author(s): 嬉野 博志、渡邉 達郎、通山 薫、岡田 誠治、原田 浩徳、牛島 俊和、木村 晋也
  • Organizer: 第78回日本癌学会学術集会
• [Presentation] reatment-Free Remission In Patients With Chronic Myelogenous Leukemia Following First-Line Dasatinib, 1st DADI/IMIDAS4 (2019)
  • Author(s): Murai K, Kimura S, Imagawa J, Hino M, Kitawaki T, Okada M, Tanaka H, Shindo M, Kumagai T, Ikezoe T, Uoshima N, Sato T, Watanabe R, Kowata S, Hayakawa M, Hosoki T, Ikeda K, Kobayashi T, Kakinoki Y,Nishimoto T, Takezako N, Shibayama H, Takaori A, Nakamae H, Kawaguchi A, Ureshino H, Sakamoto J, Ishida Y
  • Organizer: 24th European Hematology Association Congress
  • Int'l Joint Research
• [Presentation] 免疫学から見たモガムリズマブの薬理作用 (2019)
  • Author(s): 嬉野 博志
  • Organizer: 第40回日本臨床薬理学会総会
  • Invited