造血細胞移植関連遺伝子多型機能に基づく免疫制御性マイクロRNAの探索

2020 Fiscal Year Research-status Report

• Project/Area Number: 18K08343
• Research Institution: Aichi Medical University
• Principal Investigator: 高見 昭良 愛知医科大学, 医学部, 教授 (80324078)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Keywords: 造血幹細胞移植 / 遺伝子多型

Outline of Annual Research Achievements

前年度までに、複数のToll様受容体（TLR）関連多型遺伝子が、同種移植後転帰に関連するとわかった。そこで、TLR機能を統合するUNC-93B1遺伝子多型rs308328 (T>C)に着目し、非血縁者間同種骨髄移植を受けた血液がん237例（急性骨髄性白血病115例、急性リンパ性白血病46例、骨髄異形成症候群38例、悪性リンパ腫24例、慢性骨髄性白血病10例、骨髄増殖性腫瘍3例、多発性骨髄腫1例）を対象に、UNC-93B1遺伝子多型と移植後転帰との関連を検討した（Genes Immun 2021）。UNC93B1 C/C型（=低誘導能型）ドナーからの移植は、UNC93B1 C/T or T/T型（=高誘導能型）ドナーより、無病生存率が有意に高く（77% vs. 58%; p<0.01）、感染症死亡も少ない傾向がみられた。これは、TLR系の過剰応答が、移植後致死的合併症に関連する可能性を示し、今後の新規治療開発につながると期待される。
さらに、血管内皮細胞関連遺伝子多型、特にADAMTS13 rs2285489が、同種造血幹細胞移植後急性白血病再発抑制に関連するとわかり（Int J Mol Sci 2019）、機能解析に着手した。同種移植後再発の予防・治療は、同種移植最大のアンメットニーズであり、重要と考える。血中ADAMTS13濃度が低い白血病・同種移植患者の予後は不良とされているが、in vitroでリコンビナントADAMTS13を加えても、白血病への同種免疫効果や抗がん剤の効果は高まらなかった（未発表データ）。ADAMTS13遺伝子多型自体、あるいはADAMTS13発現にかかわる血管内皮細胞の分子やシグナル経路が、抗白血病効果の誘導にかかわっていると考え、ゲノム編集によるADAMTS13遺伝子多型改変ヒト血管内皮細胞クローン樹立を計画している。

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

免疫調整遺伝子多型の臨床・機能解析や同種移植成績の最適化研究研究は概ね順調に推移し、論文化も進んでいる。同種造血幹細胞移植におけるマイクロRNA制御解析等に関しては、新型コロナウイルス問題を含む社会的状況変化の影響も否定できないところであるが、検体収集を含め全体にやや遅れている。

Strategy for Future Research Activity

同種造血幹細胞移植におけるマイクロRNA制御機構解明の基盤となる臨床・基礎研究の成果は蓄積され、今後同種造血幹細胞移植成績の向上や新規治療法開発に寄与する成果も得られている。免疫制御性マイクロRNAを効率よくスクリーニング・同定するには、検体収集の加速化が不可欠である。患者リクルートを強化（インターネットなども積極的に活用）すると同時に、健常人や細胞株の収集も積極的に行う。

Research Products

• [Journal Article] Primary cutaneous methotrexate-associated B-cell lymphoproliferative disorders other than EBV-positive mucocutaneous ulcer: clinical, pathological, and immunophenotypic features (2021)
  • Author(s): Satou Akira、Banno Shogo、Kohno Kei、Takahara Taishi、Takahashi Emiko、Nobata Hironobu、Iwagaitsu Shiho、Watanabe Daisuke、Hanamura Ichiro、Takami Akiyoshi、Ito Yasuhiko、Nakamura Shigeo、Tsuzuki Toyonori
  • Journal Title: Pathology Volume: 53 Pages: 595～601
  • DOI: 10.1016/j.pathol.2020.10.019
  • Peer Reviewed
• [Journal Article] Pretreatment Immature Platelet Fraction as a Surrogate of Reticulated Platelets Predicts the Response to Corticosteroids in Adults with Immune Thrombocytopenia (2021)
  • Author(s): Takami Akiyoshi、Mizuno Shohei、Nakamura Ayano、Kanasugi Jo、Yamamoto Hidesuke、Vu?Quang Lam、Nakagami Yuya、Nakano Yuta、Yamada Saki、Matsumura Saori、Takasugi Souichi、Uchino Kaori、Horio Tomohiro、Murakami Satsuki、Oohigashi Yuka、Nakayama Takayuki、Tani Hiroya、Enomoto Megumi、Hanamura Ichiro
  • Journal Title: Acta Haematologica Volume: 144 Pages: 345～349
  • DOI: 10.1159/000510460
  • Peer Reviewed
• [Journal Article] Reference intervals of white blood cell parameters for healthy adults in japan (2021)
  • Author(s): Takami Akiyoshi、Watanabe Shinichiro、Tohyama Kaoru、The Japanese Society for Laboratory Hematology subcommittee on Standardization of Blood Cell Morphology (JSLH‐SBCM)
  • Journal Title: International Journal of Laboratory Hematology Volume: 43 Pages: 948～958
  • DOI: 10.1111/ijlh.13486
  • Peer Reviewed
• [Journal Article] Allogeneic hematopoietic cell transplantation efficacy in patients with Philadelphia chromosome-positive acute myeloid leukemia in complete remission (2021)
  • Author(s): Mizuno Shohei、Yanada Masamitsu、Kawamura Koji、Masuko Masayoshi、Uchida Naoyuki、Ozawa Yukiyasu、Iwato Koji、Ohashi Kazuteru、Ikegame Kazuhiro、Kim Sung-Won、Tanaka Masatsugu、Eto Tetsuya、Kanda Yoshinobu、Fukuda Takahiro、Atsuta Yoshiko、Yano Shingo、Takami Akiyoshi
  • Journal Title: Bone Marrow Transplantation Volume: 56 Pages: 232～242
  • DOI: 10.1038/s41409-020-01011-0
  • Peer Reviewed
• [Journal Article] Allogeneic Hematopoietic Cell Transplantation for Adolescent and Young Adult Patients with Acute Myeloid Leukemia (2021)
  • Author(s): Mizuno Shohei、Takami Akiyoshi、Kawamura Koji、Arai Yasuyuki、Kondo Tadakazu、Kawata Takahito、Uchida Naoyuki、Marumo Atsushi、Fukuda Takahiro、Tanaka Masatsugu、Ozawa Yukiyasu、Yoshida Shuro、Ota Shuichi、Takada Satoru、Sawa Masashi、Onizuka Makoto、Kanda Yoshinobu、Ichinohe Tatsuo、Atsuta Yoshiko、Yanada Masamitsu
  • Journal Title: Transplantation and Cellular Therapy Volume: 27 Pages: 314.e1～314.e10
  • DOI: 10.1016/j.jtct.2020.12.013
  • Peer Reviewed
• [Journal Article] Comparison of Transplantation Outcomes after Foscarnet and Ganciclovir Administration as First-Line Anti-Cytomegalovirus Preemptive Therapy (2021)
  • Author(s): Miyao Kotaro、Terakura Seitaro、Ozawa Yukiyasu、Sawa Masashi、Kohno Akio、Kasahara Senji、Iida Hiroatsu、Ino Kazuko、Kusumoto Shigeru、Kasai Masanobu、Takami Akiyoshi、Kurahashi Shingo、Kajiguchi Tomohiro、Morishita Takanobu、Nishida Tetsuya、Murata Makoto
  • Journal Title: Transplantation and Cellular Therapy Volume: 27 Pages: 342.e1～342.e10
  • DOI: 10.1016/j.jtct.2020.12.012
  • Peer Reviewed
• [Journal Article] Donor UNC-93 Homolog B1 genetic polymorphism predicts survival outcomes after unrelated bone marrow transplantation (2021)
  • Author(s): Uchino Kaori、Vu Quang Lam、Mizuno Shohei、Horio Tomohiro、Yamamoto Hidesuke、Hanamura Ichiro、Kodera Yoshihisa、Luis Espinoza J.、Onizuka Makoto、Kashiwase Koichi、Morishima Yasuo、Fukuda Takahiro、Doki Noriko、Miyamura Koichi、Mori Takehiko、Morishita Eriko、Nakao Shinji、Takami Akiyoshi
  • Journal Title: Genes &amp; Immunity Volume: 22 Pages: 35～43
  • DOI: 10.1038/s41435-021-00122-y
  • Peer Reviewed
• [Journal Article] CD52 is a novel target for the treatment of FLT3-ITD-mutated myeloid leukemia (2021)
  • Author(s): Hanamura, I. Karnan, S. Ota, A. Takasugi, S. Nakamura, A. Takahashi, M. Uchino, K. Murakami, S. Wahiduzzaman, M. Quan, L.V. Rahman, L. Hasanm M. Hyodo, t. Konishi, H. Tsuzuki, S. Yoshikawa, K. Suzuki, S. Ueda, R. Ejiri, M. Hosokawa, Y. Takami, A.
  • Journal Title: Cell Death Discovery Volume: 1 Pages: 1-10
  • Peer Reviewed
• [Journal Article] Antioxidant, Anti-tyrosinase, Anti-α-amylase, and Cytotoxic Potentials of the Invasive Weed Andropogon virginicus (2020)
  • Author(s): Anh La Hoang、Quan Nguyen Van、Lam Vu Quang、Iuchi Yu、Takami Akiyoshi、Teschke Rolf、Xuan Tran Dang
  • Journal Title: Plants Volume: 10 Pages: 69～69
  • DOI: 10.3390/plants10010069
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Donor Heme Oxygenase-1 Promoter Gene Polymorphism Predicts Survival after Unrelated Bone Marrow Transplantation for High-Risk Patients (2020)
  • Author(s): Horio Tomohiro、Morishita Eriko、Mizuno Shohei、Uchino Kaori、Hanamura Ichiro、Espinoza J. Luis、Morishima Yasuo、Kodera Yoshihisa、Onizuka Makoto、Kashiwase Koichi、Fukuda Takahiro、Doki Noriko、Miyamura Koichi、Mori Takehiko、Nakao Shinji、Takami Akiyoshi
  • Journal Title: Cancers Volume: 12 Pages: 424～424
  • DOI: 10.3390/cancers12020424
  • Peer Reviewed / Open Access
• [Journal Article] Pathological and Virological Studies of p16-Positive Oropharyngeal Carcinoma with a Good Response to Neoadjuvant Chemotherapy (2020)
  • Author(s): Inukai Daisuke、Kan Taichi、Yamanaka Shunpei、Okamoto Hiroki、Fujimoto Yasushi、Ito Takanori、Taniguchi Natsuki、Yamamoto Yuuki、Tsuzuki Toyonori、Takami Akiyoshi、Ogawa Tetsuya
  • Journal Title: Microorganisms Volume: 8 Pages: 1497～1497
  • DOI: 10.3390/microorganisms8101497
  • Peer Reviewed / Open Access
• [Journal Article] Reduced-intensity stem cell transplantation for acute myeloid leukemia with fludarabine-based conditioning with intravenous busulfan versus melphalan (2020)
  • Author(s): Yamashita Takuya、Takami Akiyoshi、Uchida Naoyuki、Fukuda Takahiro、Eto Tetsuya、Shiratori Souichi、Ota Shuichi、Akasaka Takashi、Miyakoshi Shigesaburo、Kondo Tadakazu、Hidaka Michihiro、Kanda Junya、Atsuta Yoshiko、Yano Shingo
  • Journal Title: Bone Marrow Transplantation Volume: 55 Pages: 1955～1965
  • DOI: 10.1038/s41409-020-0856-y
  • Peer Reviewed
• [Journal Article] Allogeneic hematopoietic cell transplantation for adults with acute myeloid leukemia conducted in Japan during the past quarter century (2020)
  • Author(s): Yanada Masamitsu、Takami Akiyoshi、Yamasaki Satoshi、Arai Yasuyuki、Konuma Takaaki、Uchida Naoyuki、Najima Yuho、Fukuda Takahiro、Tanaka Masatsugu、Ozawa Yukiyasu、Ikegame Kazuhiro、Takanashi Minoko、Ichinohe Tatsuo、Okamoto Shinichiro、Atsuta Yoshiko、Yano Shingo
  • Journal Title: Annals of Hematology Volume: 99 Pages: 1351～1360
  • DOI: 10.1007/s00277-020-04051-0
  • Peer Reviewed
• [Journal Article] Autologous hematopoietic cell transplantation for acute myeloid leukemia in adults: 25?years of experience in Japan (2020)
  • Author(s): Yanada Masamitsu、Takami Akiyoshi、Mizuno Shohei、Mori Jinichi、Chou Takaaki、Usuki Kensuke、Uchiyama Hitoji、Amano Itsuto、Fujii Shiro、Miyamoto Toshihiro、Saito Takeshi、Kamimura Tomohiko、Ichinohe Tatsuo、Fukuda Takahiro、Okamoto Shinichiro、Atsuta Yoshiko、Yano Shingo
  • Journal Title: International Journal of Hematology Volume: 111 Pages: 93～102
  • DOI: 10.1007/s12185-019-02759-y
  • Peer Reviewed
• [Journal Article] Juvenile Hemochromatosis: A Case Report and Review of the Literature (2020)
  • Author(s): Takami Akiyoshi、Tatsumi Yasuaki、Sakai Katsuhisa、Toki Yasumichi、Ikuta Katsuya、Oohigashi Yuka、Takagi Junko、Kato Koichi、Takami Kazuhisa
  • Journal Title: Pharmaceuticals Volume: 13 Pages: 195～195
  • DOI: 10.3390/ph13080195
  • Peer Reviewed / Open Access
• [Journal Article] Reply to the letter by Gaetano Loscocco, Secondary hemophagocytic lymphohistiocytosis, HScore and COVID-19 (2020)
  • Author(s): Takami Akiyoshi
  • Journal Title: International Journal of Hematology Volume: 112 Pages: 127～127
  • DOI: 10.1007/s12185-020-02896-9
  • Peer Reviewed
• [Journal Article] Possible role of low-dose etoposide therapy for hemophagocytic lymphohistiocytosis by COVID-19 (2020)
  • Author(s): Takami Akiyoshi
  • Journal Title: International Journal of Hematology Volume: 112 Pages: 122～124
  • DOI: 10.1007/s12185-020-02888-9
  • Peer Reviewed
• [Journal Article] Novel Interleukin-6 Inducible Gene PDZ-Binding Kinase Promotes Tumor Growth of Multiple Myeloma Cells (2020)
  • Author(s): Ota Akinobu、Hanamura Ichiro、Karnan Sivasundaram、Inaguma Shingo、Takei Norio、Lam Vu Quang、Mizuno Shohei、Kanasugi Jo、Wahiduzzaman Md、Rahman Md Lutfur、Hyodo Toshinori、Konishi Hiroyuki、Tsuzuki Shinobu、Ikeda Hiroshi、Takami Akiyoshi、Hosokawa Yoshitaka
  • Journal Title: Journal of Interferon & Cytokine Research Volume: 40 Pages: 389～405
  • DOI: 10.1089/jir.2020.0111
  • Peer Reviewed
• [Journal Article] In vivo tracking of transplanted macrophages with near infrared fluorescent dye reveals temporal distribution and specific homing in the liver that can be perturbed by clodronate liposomes (2020)
  • Author(s): Nishiwaki Satoshi、Saito Shigeki、Takeshita Kyosuke、Kato Hidefumi、Ueda Ryuzo、Takami Akiyoshi、Naoe Tomoki、Ogawa Mika、Nakayama Takayuki
  • Journal Title: PLOS ONE Volume: 15 Pages: e0242488
  • DOI: 10.1371/journal.pone.0242488
  • Peer Reviewed / Open Access
• [Journal Article] Potential role of Howell?Jolly bodies in identifying functional hyposplenism: a prospective single-institute study (2020)
  • Author(s): Nakagami Yuya、Uchino Kaori、Okada Hiroaki、Suzuki Kojiro、Enomoto Megumi、Mizuno Shohei、Yamamoto Hidesuke、Hanamura Ichiro、Nakayama Takayuki、Tani Hiroya、Takami Akiyoshi
  • Journal Title: International Journal of Hematology Volume: 112 Pages: 544～552
  • DOI: 10.1007/s12185-020-02925-7
  • Peer Reviewed
• [Journal Article] Combining T‐cell‐based immunotherapy with venetoclax elicits synergistic cytotoxicity to B‐cell lines in vitro (2020)
  • Author(s): Murakami Satsuki、Suzuki Susumu、Hanamura Ichiro、Yoshikawa Kazuhiro、Ueda Ryuzo、Seto Masao、Takami Akiyoshi
  • Journal Title: Hematological Oncology Volume: 38 Pages: 705～714
  • DOI: 10.1002/hon.2794
  • Peer Reviewed
• [Journal Article] Outcome and Risk Factors for Therapy-Related Myeloid Neoplasms Treated with Allogeneic Stem Cell Transplantation in Japan (2020)
  • Author(s): Kida Michiko、Usuki Kensuke、Uchida Naoyuki、Fukuda Takahiro、Katayama Yuta、Kondo Tadakazu、Eto Tetsuya、Matsuoka Ken-ichi、Matsuhashi Yoshiko、Ota Shuichi、Sawa Masashi、Miyamoto Toshihiro、Ichinohe Tatsuo、Kimura Takafumi、Atsuta Yoshiko、Takami Akiyoshi
  • Journal Title: Biology of Blood and Marrow Transplantation Volume: 26 Pages: 1543～1551
  • DOI: 10.1016/j.bbmt.2020.04.004
  • Peer Reviewed
• [Journal Article] Uterine relapse of Philadelphia chromosome-negative acute lymphoblastic leukemia (2020)
  • Author(s): Kawano Noriaki、Maeda Tetsuo、Kawano Sayaka、Naghiro Yuri、Takami Akiyoshi、Tochigi Taro、Nakaike Takashi、Yamashita Kiyoshi、Kodama Takao、Marutsuka Kosuke、Sugimoto Yuka、Imamura Toshihiko、Mori Yasuo、Ochiai Hidenobu、Hidaka Tomonori、Shimoda Kazuya、Mashiba Koichi、Kikuchi Ikuo
  • Journal Title: Journal of Clinical and Experimental Hematopathology Volume: 60 Pages: 103～107
  • DOI: 10.3960/jslrt.20016
  • Peer Reviewed
• [Journal Article] Resveratrol improves motor function in patients with muscular dystrophies: an open-label, single-arm, phase IIa study (2020)
  • Author(s): Kawamura Kentaro、Fukumura Shinobu、Nikaido Koki、Tachi Nobutada、Kozuka Naoki、Seino Tsugumi、Hatakeyama Kingya、Mori Mitsuru、Ito Yoichi M.、Takami Akiyoshi、Hinotsu Shiro、Kuno Atsushi、Kawasaki Yukihiko、Horio Yoshiyuki、Tsutsumi Hiroyuki
  • Journal Title: Scientific Reports Volume: 10 Pages: 1-10
  • DOI: 10.1038/s41598-020-77197-6
  • Peer Reviewed / Open Access
• [Journal Article] Biallelic loss of FAM46C triggers tumor growth with concomitant activation of Akt signaling in multiple myeloma cells (2020)
  • Author(s): Kanasugi Jo、Hanamura Ichiro、Ota Akinobu、Karnan Sivasundaram、Lam Vu Quang、Mizuno Shohei、Wahiduzzaman Md、Rahman Md Lutfur、Hyodo Toshinori、Konishi Hiroyuki、Tsuzuki Shinobu、Hosokawa Yoshitaka、Takami Akiyoshi
  • Journal Title: Cancer Science Volume: 111 Pages: 1663～1675
  • DOI: 10.1111/cas.14386
  • Peer Reviewed
• [Presentation] 臨床血液・形態学入門 (2020)
  • Author(s): 高見昭良
  • Organizer: 日本検査血液学会学術集会
  • Invited