Analysis of regulation of signals by STAP adaptor protein in immune system and tumorigenesis

• Project/Area Number: 16K09872
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: International University of Health and Welfare (2017-2018); Osaka University (2016)
• Principal Investigator: ORITANI KENJI 国際医療福祉大学, 医学部, 教授 (70324762)
• Co-Investigator(Kenkyū-buntansha): 前田 哲生 大阪大学, 医学系研究科, 助教 (00403064) ; 金倉 譲 大阪大学, 医学系研究科, 教授 (20177489) ; 一井 倫子 大阪大学, 医学系研究科, 寄附講座助教 (30633010) ; 戸田 淳 大阪大学, 医学部附属病院, 医員 (90770834)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: STAP / アダプター蛋白 / 免疫応答 / 慢性骨髄性白血病 / 移植片対宿主病 / 造血幹細胞移植 / 免疫反応 / 腫瘍化 / シグナル伝達 / 炎症反応 / GVHD / T細胞受容体 / 遺伝子 / 蛋白質 / 免疫学 / 内科

Outline of Final Research Achievements

We analyzed functional mechanisms of adaptor protein STAP and possible involvement in disease development.
We newly found positive regulation of T-cell receptor signals by STAP through its binding to LCK and CD3-ITAM. We also showed that STAP is involved in maintenance of chronic myelocytic leukemia stem cells. We established GVHD experimental model using STAP-transgenic mouse, and found that over-expression of STAP in T-lymphocytes highly enhanced clinical symptoms of graft-versus-host disease.
Therefore, we could show potential of clinical utilities of STAP-inhibitors in the fields of the elimination of chronic myelocytic leukemia stem cells and the prevention and treatment of graft-versus-host disease after allogenic hematopoietic stem cell transplantation.

Academic Significance and Societal Importance of the Research Achievements

STAPアダプター蛋白の免疫応答への関与を明らかにするとともに、慢性骨髄性白血病や移植片宿主病の病因・病態へのSTAPの関与を明らかにした。このことは、自己免疫疾患などの難治性疾患や一部の腫瘍において、STAP人為的操作による治療の可能性を示唆するものである。STAP阻害剤開発後の治療対象疾患の縛り込みに成功した。

Research Products

• [Journal Article] STAP-2 positively regulates FcεRI-mediated basophil activation and basophil-dependent allergic inflammatory reactions (2019)
  • Author(s): Kashiwakura Jun-ichi、Yamashita Shinsuke、Yoshihara Mari、Inui Kyosuke、Saitoh Kodai、Sekine Yuichi、Muromoto Ryuta、Kitai Yuichi、Oritani Kenji、Matsuda Tadashi
  • Journal Title: International Immunology Volume: 31 Issue: 5 Pages: 349-356
  • DOI: 10.1093/intimm/dxz013
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Variable SATB1 Levels Regulate Hematopoietic Stem Cell Heterogeneity with Distinct Lineage Fate (2018)
  • Author(s): Yukiko Doi, Takafumi Yokota, Yusuke Satoh, Daisuke Okuzaki, Masahiro Tokunaga, Tomohiko Ishibashi, Takao Sudo, Tomoaki Ueda, Yasuhiro Shingai, Michiko Ichii, Akira Tanimura, Sachiko Ezoe, Hirohiko Shibayama, Terumi Kohwi-Shigematsu, Junji Takeda, Kenji Oritani, and Yuzuru Kanakura
  • Journal Title: Cell Reports Volume: 23 Issue: 11 Pages: 3223-3235
  • DOI: 10.1016/j.celrep.2018.05.042
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Effect of ruxolitinib therapy on the quality of life of Japanese patients with myelofibrosis. (2018)
  • Author(s): Oritani K, Ohishi K, Okamoto S, Kirito K, Komatsu N, Tauchi T, Handa H, Saito S, Takenaka K, Shimoda K, Okada H, Amagasaki T, Wakase S, Shimozuma K, Akashi K
  • Journal Title: Curr Med Res Opin Volume: 34 Issue: 3 Pages: 531-537
  • DOI: 10.1080/03007995.2017.1415874
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Evaluation of the dose and efficacy of ruxolitinib in Japanese patients with myelofibrosis. (2018)
  • Author(s): Kirito K, Okamoto S, Ohishi K, Tauchi T, Handa H, Saito S, Takenaka K, Shimoda K, Oritani K, Akashi K, Okada H, Amagasaki T, Suzuki K, Yonezu T, Komatsu N
  • Journal Title: Int J Hematol Volume: 107(1) Issue: 1 Pages: 92-97
  • DOI: 10.1007/s12185-017-2332-z
  • Peer Reviewed / Open Access
• [Journal Article] Molecular targeting of inosine-5'-monophosphate dehydrogenase by FF-10501 promotes erythropoiesis via ROS/MAPK pathway. (2018)
  • Author(s): Ichii M, Oritani K, Murase M, Komatsu K, Yamazaki M, Kyoden R, Kito N, Nozaki Y, Saito M, Iwamura H, Kanakura Y
  • Journal Title: Leuk Lymphoma Volume: 59(2) Issue: 2 Pages: 448-459
  • DOI: 10.1080/10428194.2017.1339878
  • Peer Reviewed / Open Access
• [Journal Article] STAP-2 protein promotes prostate cancer growth by enhancing epidermal growth factor receptor stabilization. (2017)
  • Author(s): Kitai Y, Iwakami M, Saitoh K, Togi S, Isayama S, Sekine Y, Muromoto R, Kashiwakura JI, Yoshimura A, Oritani K, Matsuda T
  • Journal Title: J Biol Chem Volume: 292(47) Issue: 47 Pages: 19392-19399
  • DOI: 10.1074/jbc.m117.802884
  • NAID: 120006539248
  • Peer Reviewed / Open Access
• [Journal Article] STAP-2 interacts with Pyk2 and enhances Pyk2 activity in T-cells. (2017)
  • Author(s): Saitoh K, Tsuchiya T, Kashiwakura JI, Muromoto R, Kitai Y, Sekine Y, Oritani K, Matsuda T
  • Journal Title: Biochem Biophys Res Commun Volume: 488(1) Issue: 1 Pages: 81-87
  • DOI: 10.1016/j.bbrc.2017.05.010
  • NAID: 120006477491
  • Peer Reviewed / Open Access
• [Journal Article] Endothelial cell-selective adhesion molecule expression in hematopoietic stem/progenitor cells is essential for erythropoiesis recovery after bone marrow injury. (2016)
  • Author(s): Sudo T, Yokota T, Okuzaki D, Ueda T, Ichii M, Ishibashi T, Isono T, Habuchi Y, Oritani K, Kanakura Y.
  • Journal Title: PLoS One Volume: 11 Issue: 4 Pages: e0154189-e0154189
  • DOI: 10.1371/journal.pone.0154189
  • Peer Reviewed / Open Access
• [Journal Article] Caspase-dependent cleavage regulates protein levels of Epstein-Barr virus-derived latent membrane protein 1. (2016)
  • Author(s): Togi S, Hatano Y, Muromoto R, Kawanishi E, Ikeda O, Hirashima K, Kon S, Kitai Y, Yasui T, Oritani K, Matsuda T.
  • Journal Title: FEBS Lett. Volume: 590 Issue: 6 Pages: 808-818
  • DOI: 10.1002/1873-3468.12119
  • NAID: 120005981517
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] ESAM is a novel human hematopoietic stem cell marker associated with a subset of human leukemias. (2016)
  • Author(s): Ishibashi T, Yokota T, Tanaka H, Ichii M, Sudo T, Satoh Y, Doi Y, Ueda T, Tanimura A, Hamanaka Y, Ezoe S, Shibayama H, Oritani K, Kanakura Y.
  • Journal Title: Experimental Hematology Volume: 44 Issue: 4 Pages: 269-281
  • DOI: 10.1016/j.exphem.2015.12.010
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Ectonucleosidase CD39 Is Highly Expressed on ATLL Cells and Suppresses the Immune Response through theAdenosine Pathway. (2018)
  • Author(s): Yasuhiro Nagate, Sachiko Ezoe, Jiro Fujita, Takafumi Yokota, Michiko Ichii, Akira Tanimura, Yukiko Doi, Tomoaki Ueda, Jun Toda, Hirohiko Shibayama, Kenji Oritani, Yuzuru Kanakura
  • Organizer: The American Society of Hematology 60th Annual Meeting (2018.12.1-4, San Diego Convention Center, CA, USA)
  • Int'l Joint Research
• [Presentation] ESAM on the Cells of Endothelial Lineage Plays an Important Role in the Development of Definitive Hematopoiesis. (2018)
  • Author(s): Tomoaki Ueda, Takafumi Yokota, Yoshihiro Uno, Tomoji Mashimo, Takao Sudo, Tomohiko Ishibashi, Yukiko Doi1, Yasuhiro Shingai, Akira Tanimura, Michiko Ichii, Sachiko Ezoe, Hirohiko Shibayama, Kenji Oritani, Yuzuru Kanakura
  • Organizer: The American Society of Hematology 60th Annual Meeting (2018.12.1-4, San Diego Convention Center, CA, USA)
  • Int'l Joint Research
• [Presentation] Role of Signal Transducing Adaptor Protein-1 (STAP-1) in Chronic Myelogenous Leukemia. (2018)
  • Author(s): Jun Toda, Michiko Ichii, Kenji Oritani, Hideaki Saito, Yuichi Kitai, Ryuta Muromoto, Jun-ichi Kashiwakura, Kodai Saitoh, Tadashi Matsuda, Yuzuru Kanakura
  • Organizer: The American Society of Hematology 60th Annual Meeting (2018.12.1-4, San Diego Convention Center, CA, USA)
  • Int'l Joint Research
• [Presentation] Signal Transducing Adaptor Protein (STAP) Family Accelerates Gut and Thymic Graft-Versus-Host-Disease in Murine Model. (2018)
  • Author(s): Hideaki Saito, Michiko Ichii, Jun Toda, Yuichi Kitai, Ryuta Muromoto, Jun-ichi Kashiwakura, Kodai Saitoh, Hirohiko Shibayama, Tadashi Matsuda, Kenji Oritani, Yuzuru Kanakura
  • Organizer: The American Society of Hematology 60th Annual Meeting (2018.12.1-4, San Diego Convention Center, CA, USA)
  • Int'l Joint Research
• [Presentation] 骨髄内B細胞分化におけるSTAP-2蛋白の役割 (2018)
  • Author(s): 一井倫子, 織谷健司, 柴山浩彦, 戸田 淳, 西東秀晃, 北井勇一, 室本竜太, 柏倉淳一, 齋藤浩大, 松田 正, 金倉 譲
  • Organizer: 第80回日本血液学会学術集会 （2018.10.12-14, 大阪国際会議場, 大阪, 松村到）
• [Presentation] クロマチン構造制御蛋白SATB1はリンパ球分化における造血幹細胞の機能的ゆらぎに関与する (2018)
  • Author(s): 土居由貴子, 横田貴史, 佐藤友亮, 石橋知彦, 数藤孝雄, 上田智朗, 新開泰宏, 小澤孝幸, 一井倫子, 谷村 朗, 江副幸子, 柴山浩彦, Terumi Kohwi-Shigematsu, 織谷健司, 金倉 譲
  • Organizer: 第80回日本血液学会学術集会 （2018.10.12-14, 大阪国際会議場, 大阪, 松村到）
• [Presentation] ATLL細胞はCD39を高発現し、Adenosine経路を介して免疫応答を抑制する (2018)
  • Author(s): 長手泰宏, 江副幸子, 藤田二郎, 横田貴史, 一井倫子, 谷村 朗, 濱中 有理, 土居由貴子, 上田智朗, 戸田 淳, 柴山浩彦, 織谷健司, 金倉 譲
  • Organizer: 第80回日本血液学会学術集会 （2018.10.12-14, 大阪国際会議場, 大阪, 松村到）
• [Presentation] 慢性骨髄性白血病におけるSTAPファミリー蛋白の役割 (2018)
  • Author(s): 戸田 淳, 一井倫子, 西東秀晃, 鍛代悠一,室本竜太, 柏倉淳一, 齋藤浩大, 柴山浩彦, 松田 正, 織谷健司, 金倉 譲
  • Organizer: 第80回日本血液学会学術集会 （2018.10.12-14, 大阪国際会議場, 大阪, 松村到）
• [Presentation] 造血幹細胞移植後腸内細菌叢のUniFrac解析をもとにした検討 (2018)
  • Author(s): 草壁信輔, 前田哲生, 中井りつこ, 日野彬央, 長手泰宏, 福島健太郎, 藤田二郎, 元岡大佑, 中村昇太, 柴山浩彦, 織谷健司, 金倉 譲
  • Organizer: 第80回日本血液学会学術集会 （2018.10.12-14, 大阪国際会議場, 大阪, 松村到）
• [Presentation] Signal transducing adaptor protein-2(STAP-2)はマウスモデルで慢性GVHDを悪化させる (2018)
  • Author(s): 西東秀晃, 一井倫子,戸田 淳, 鍛代悠一, 室本竜太, 柏倉淳一, 齋藤浩大, 柴山浩彦, 松田 正, 織谷健司, 金倉 譲
  • Organizer: 第80回日本血液学会学術集会 （2018.10.12-14, 大阪国際会議場, 大阪, 松村到）
• [Presentation] 異常なRTKの細胞内輸送阻害は急性骨髄性白血病における有望な治療標的である (2018)
  • Author(s): 頼 晋也, 田中宏和, 鈴木麻衣, Luis Espinoza, 谷村 朗, 森田泰慶, 辰巳陽一, 横田貴史, 織谷健司, 渡邊俊雄, 金倉 譲, 松村 到
  • Organizer: 第80回日本血液学会学術集会 （2018.10.12-14, 大阪国際会議場, 大阪, 松村到）
• [Presentation] Signal transducing adaptor protein-1(STAP-1)maintains chronic myeloid leukemic stem cells. (2017)
  • Author(s): Toda J, Ichii M, Oritani K, Saito H, Kitai Y, Muromoto R, Kashiwakura J, Saitoh K, Matsuda T, Kanakura Y
  • Organizer: 22nd Congress of the European Hematology Association
  • Int'l Joint Research
• [Presentation] Signal-Transducing Adaptor Protein-2 Blocks B cell Recovery under Hematological Stress at pre-B stage via TLR4 Signaling. (2017)
  • Author(s): Ichii M, Oritani K, Shibayama H, Toda J, Saito H, Kitai Y, Muromoto R, Kashiwakura J, Saitoh K, Matsuda T, Kanakura Y
  • Organizer: The American Society of Hematology 59th Annual Meeting
  • Int'l Joint Research
• [Presentation] Role of Signal Transducing Adaptor Protein (STAP) Family in Chronic Myelogenous Leukemia. (2017)
  • Author(s): Toda J, Ichii M, Shibayama H, Saito H, Kitai Y, Muromoto R, Kashiwakura J, Saitoh K, Matsuda T, Oritani K, Kanakura Y
  • Organizer: The American Society of Hematology 59th Annual Meeting
  • Int'l Joint Research
• [Presentation] 慢性骨髄性白血病の進展におけるアダプター蛋白STAP-1の役割 (2017)
  • Author(s): Toda J, Ichii M, Oritani K, Saito H, Kitai Y, Muromoto R, Kashiwakura J, Saitoh K, Matsuda T, Kanakura Y
  • Organizer: 第79回日本血液学会学術集会
• [Presentation] STAP-2 is an adopter molecule to positively regulate basophil activation (2017)
  • Author(s): Jun-ichi Kashiwakura, Shinsuke Yamashita, Kodai Saitoh, Kenji Oritani and Tadashi Matsuda
  • Organizer: 第46回日本免疫学会学術集会
• [Presentation] T細胞活性化及び免疫応答におけるSTAP-2の機能解析 (2016)
  • Author(s): 齋藤 浩大、織谷健司 他
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜 (神奈川県、横浜市)
  • Year and Date: 2016-11-30
• [Presentation] STAP-2によるTCRシグナル及び免疫応答制御機構の解明 (2016)
  • Author(s): 齋藤 浩大、織谷健司 他
  • Organizer: 第53回日本生化学会北海道支部例会
  • Place of Presentation: 鈴木章ホール （北海道、札幌市）
  • Year and Date: 2016-07-08
• [Book] WHO血液腫瘍分類 (2018)
  • Author(s): 織谷健司ら、計114名
  • Total Pages: 463
  • Publisher: 医薬ジャーナル社
  • ISBN: 9784753228713
• [Remarks] 血液・腫瘍内科学ホームページ
  • URL: http://www.hematology.pro
• [Patent(Industrial Property Rights)] 移植片対宿主病モデル動物、及び移植片対宿主病の治療剤のスクリーニング方法 (2018)
  • Inventor(s): 松田 正、織谷健司、一井倫子
  • Industrial Property Rights Holder: 松田 正、織谷健司、一井倫子
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2018-170771
  • Filing Date: 2018