造血幹細胞移植関連遺伝子多型の機能解析とゲノム標的治療の探索

2015 Fiscal Year Research-status Report

• Project/Area Number: 15K09513
• 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): 2015-04-01 – 2018-03-31
• Keywords: 造血幹細胞移植 / 一塩基多型

Outline of Annual Research Achievements

造血幹細胞移植は血液難病の根治療法である。本研究の最終目標は、造血幹細胞移植成功率を飛躍的に高めることにある。免疫調整遺伝子多型解析をもとに最善のドナーを選び、移植後合併症を予測し予防するテーラーメード型移植法を確立するため、日本骨髄バンクを通じた非血縁者間同種骨髄移植患者・ドナーの試料（DNA）・臨床データを用いて、遺伝子多型との関連を後方視的に検討した。平成27年度は、トロンボモジュリン・TLR1各遺伝子多型の機能的役割を見出し、同種造血幹細胞移植における臨床的影響を検証した。トロンボモジュリン誘導能が高い遺伝子多型を有するドナーから移植を受けた場合、移植片対宿主病発症率が有意に低く、死亡率も低いことがわかった。トロンボモジュリンには抗炎症作用や組織障害保護作用が期待されることから、同種造血幹細胞移植後移植片対宿主病に対するトロンボモジュリンの予防・治療効果を示唆する成果と思われる。さらにToll-like receptor (TLR) 1誘導能が高い患者、あるいはTLR1誘導能が高いドナーを有する患者の場合、移植関連死亡率が低いことがわかった。TLR1は感染免疫における役割が示唆されていることから、新規治療法開発への発展性も期待されると考えられた。さらに、TLR-2・4、CCL2、CCR5・6、IL-23R、IL-12RB各遺伝多型を決定し、解析を進めている。

Current Status of Research Progress

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

Reason

複数遺伝子多型の解析を終え、学会発表、論文投稿へと進めていることから、おおむね順調に進展していると判断した。ただし、機能解析や前向き研究は現在準備中であり、当初の予定以上に進展している状況にはない。

Strategy for Future Research Activity

後方視的結果に基づき、各遺伝子多型解析に必要な試料・臨床データ数を算出し、血縁者間造血幹細胞移植を対象に、前方視的検討を行う。さらに、臨床解析で臨床的意義が確認された多型遺伝子を対象に機能解析を行い、ゲノム機序の解明を図る。順調に推移すれば、新たに明らかとなった機能的遺伝子多型を健常人・患者の血液細胞や細胞株へ導入し、アリル特異的な抑制・増強が発現レベルやサイトカイン産生能、細胞機能に与える影響を検証する。前方視的研究への参加が不足する場合は、インターネットを用いた広報活動を強化する。遺伝子多型解析・データ解析が円滑に進まない場合は、実験補助者1名の雇用を検討する。

Research Products

• [Journal Article] Identification of a novel missense mutation (563G>a) in the ABO gene associated with a Bel phenotype (2016)
  • Author(s): Niwa, R., Nakayama, T., Ishii, H., Fujita, E., Ishiyama, K., Matsuo, T., Shimizu, A., Gao, S., Hayashi, M., Katai, A., Ando, T., Takahashi, M., Takeshita, K., Takami, A. and Kato, H.
  • Journal Title: Transfusion Volume: 56 Pages: 1242-3
  • DOI: 10.1111/trf.13507
  • Peer Reviewed
• [Journal Article] Comparable outcomes between autologous and allogeneic transplant for adult acute myeloid leukemia in first CR (2016)
  • Author(s): Mizutani, M., Hara, M., Fujita, H., Aoki, J., Kanamori, H., Ohashi, K., Usuki, K., Fukuda, T., Chou, T., Tanaka, J., Atsuta, Y. and Takami, A.
  • Journal Title: Bone Marrow Transplant Volume: 51 Pages: 645-53
  • DOI: 10.1038/bmt.2015.349
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Impact of low-dose TBI on outcomes of reduced intensity conditioning allogeneic hematopoietic stem cell transplantation for AML (2016)
  • Author(s): Aoki, J., Seo, S., Kanamori, H., Tanaka, M., Fukuda, T., Onizuka, M., Kobayashi, N., Kondo, T., Sawa, M., Uchida, N., Iwato, K., Icihnohe, T., Atsuta, Y., Yano, S. and Takami, A.
  • Journal Title: Bone Marrow Transplant Volume: 51 Pages: 604-6
  • DOI: 10.1038/bmt.2015.297
  • Peer Reviewed
• [Journal Article] Impact of age on outcomes of allogeneic hematopoietic stem cell transplantation with reduced intensity conditioning in elderly patients with acute myeloid leukemia (2016)
  • Author(s): Aoki, J., Kanamori, H., Tanaka, M., Yamasaki, S., Fukuda, T., Ogawa, H., Iwato, K., Ohashi, K., Okumura, H., Onizuka, M., Maesako, Y., Teshima, T., Kobayashi, N., Morishima, Y., Hirokawa, M., Atsuta, Y., Yano, S. and Takami, A.
  • Journal Title: Am J Hematol Volume: 91 Pages: 302-7
  • DOI: 10.1002/ajh.24270
  • Peer Reviewed
• [Journal Article] A prospective multicenter study of unrelated bone marrow transplants using a reduced-intensity conditioning regimen with low-dose ATG-F (2016)
  • Author(s): Fuji, S., Kim, S. W., Yano, S., Hagiwara, S., Nakamae, H., Hidaka, M., Ito, T., Ohashi, K., Hatanaka, K., Takami, A., Kurosawa, S., Yamashita, T., Yamaguchi, T. and Fukuda, T
  • Journal Title: Bone Marrow Transplant Volume: 51 Pages: 451-3
  • DOI: 10.1038/bmt.2015.268
  • Peer Reviewed
• [Journal Article] Unrelated bone marrow transplantation or immediate umbilical cord blood transplantation for patients with acute myeloid leukemia in first complete remission (2016)
  • Author(s): Yanada, M., Kanda, J., Ohtake, S., Fukuda, T., Sakamaki, H., Miyamura, K., Miyawaki, S., Uchida, N., Maeda, T., Nagamura-Inoue, T., Asou, N., Morishima, Y., Atsuta, Y., Miyazaki, Y., Kimura, F., Kobayashi, Y., Takami, A., Naoe, T. and Kanda, Y
  • Journal Title: Eur J Haematol Volume: NA Pages: NA
  • DOI: 10.1111/ejh.12723
  • Peer Reviewed
• [Journal Article] Paraptosis cell death induction by the thiamine analog benfotiamine in leukemia cells (2015)
  • Author(s): Sugimori, N., Espinoza, J. L., Trung, L. Q., Takami, A., Kondo, Y., An, D. T., Sasaki, M., Wakayama, T. and Nakao, S
  • Journal Title: PLoS One Volume: 10 Pages: e0120709
  • DOI: 10.1371/journal.pone.0120709
  • Peer Reviewed / Open Access
• [Journal Article] A donor thrombomodulin gene variation predicts graft-versus-host disease development and mortality after bone marrow transplantation (2015)
  • Author(s): Nomoto, H., Takami, A., Espinoza, J. L., Matsuo, K., Mizuno, S., Onizuka, M., Kashiwase, K., Morishima, Y., Fukuda, T., Kodera, Y., Doki, N., Miyamura, K., Mori, T., Nakao, S., Ohtake, S. and Morishita, E
  • Journal Title: Int J Hematol Volume: 102 Pages: 460-70
  • DOI: 10.1007/s12185-015-1852-7
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Outcomes of allogeneic hematopoietic cell transplantation in patients with biphenotypic acute leukemia (2015)
  • Author(s): Mori, J., Ishiyama, K., Yamaguchi, T., Tanaka, J., Uchida, N., Kobayashi, T., Fukuda, T., Kanamori, H., Miyamura, K., Takahashi, S., Eto, T., Hirokawa, M., Mori, S., Nagamura, T., Atsuta, Y. and Takami, A
  • Journal Title: Ann Hematol Volume: NA Pages: NA
  • DOI: 10.1007/s00277-015-2536-3
  • Peer Reviewed
• [Journal Article] Overexpression of salivary-type amylase reduces the sensitivity to bortezomib in multiple myeloma cells (2015)
  • Author(s): Mizuno, S., Hanamura, I., Ota, A., Karnan, S., Narita, T., Ri, M., Mizutani, M., Goto, M., Gotou, M., Tsunekawa, N., Shikami, M., Iida, S., Hosokawa, Y., Miwa, H., Ueda, R., Nitta, M. and Takami, A
  • Journal Title: Int J Hematol Volume: 102 Pages: 569-78
  • DOI: 10.1007/s12185-015-1859-0
  • Peer Reviewed
• [Journal Article] Effect of Granulocyte Colony-Stimulating Factor-Combined Conditioning in Cord Blood Transplantation for Myelodysplastic Syndrome and Secondary Acute Myeloid Leukemia: A Retrospective Study in Japan (2015)
  • Author(s): Konuma, T., Takahashi, S., Uchida, N., Kuwatsuka, Y., Yamasaki, S., Aoki, J., Onishi, Y., Aotsuka, N., Ohashi, K., Mori, T., Masuko, M., Nakamae, H., Miyamura, K., Kato, K., Atsuta, Y., Kato, S., Asano, S., Takami, A., Miyazaki, Y.
  • Journal Title: Biol Blood Marrow Transplant Volume: 21 Pages: 1632-40
  • DOI: 10.1016/j.bbmt.2015.05.009
  • Peer Reviewed
• [Journal Article] Successful Secondary Umbilical Cord Blood Transplantation for Graft Failure in Acute Myelogenous Leukemia, Treated with Modified One-Day Conditioning Regimen, and Graft-Versus-Host Disease Prophylaxis Consisting of Mycophenolate and Tacrolimus (2015)
  • Author(s): awano, N., Kuriyama, T., Yoshida, S., Shimizu, I., Kobayashi, H., Takenaka, K., Uchida, N., Takami, A., Yamashita, K., Ueda, A. and Kikuchi, I
  • Journal Title: J Clin Exp Hematop Volume: 55 Pages: 89-96
  • DOI: 10.3960/jslrt.55.89
  • Peer Reviewed
• [Journal Article] Increased glycosylphosphatidylinositol-anchored protein-deficient granulocytes define a benign subset of bone marrow failures in patients with trisomy 8 (2015)
  • Author(s): Hosokawa, K., Sugimori, N., Katagiri, T., Sasaki, Y., Saito, C., Seiki, Y., Mochizuki, K., Yamazaki, H., Takami, A. and Nakao, S
  • Journal Title: Eur J Haematol Volume: 95 Pages: 230-8
  • DOI: 10.1111/ejh.12484
  • Peer Reviewed
• [Journal Article] Stilbene derivatives from melinjo extract have antioxidant and immune modulatory effects in healthy individuals (2015)
  • Author(s): Espinoza, J. L., An, D. T., Trung, L. Q., Yamada, K., Nakao, S. and Takami, A
  • Journal Title: Integr Mol Med Volume: 2 Pages: 405-413
  • DOI: 10.15761/IMM.1000177
  • Peer Reviewed
• [Journal Article] Efficiency of high-dose cytarabine added to CY/TBI in cord blood transplantation for myeloid malignancy (2015)
  • Author(s): Arai, Y., Takeda, J., Aoki, K., Kondo, T., Takahashi, S., Onishi, Y., Ozawa, Y., Aotsuka, N., Kouzai, Y., Nakamae, H., Ota, S., Nakaseko, C., Yamaguchi, H., Kato, K., Atsuta, Y., Takami, A., Aml and Transplantation, M. D. S. Working Group of the Japan Society for Hematopoietic Cell
  • Journal Title: Blood Volume: 126 Pages: 415-22
  • DOI: 10.1182/blood-2015-04-642652
  • Peer Reviewed
• [Journal Article] Clinical significance of high-dose cytarabine added to cyclophosphamide/total-body irradiation in bone marrow or peripheral blood stem cell transplantation for myeloid malignancy (2015)
  • Author(s): Arai, Y., Aoki, K., Takeda, J., Kondo, T., Eto, T., Ota, S., Hashimoto, H., Fukuda, T., Ozawa, Y., Kanda, Y., Kato, C., Kurokawa, M., Iwato, K., Onizuka, M., Ichinohe, T., Atsuta, Y., Takami, A., Aml and Transplantation, M. D. S. Working Group of Japan Society for Hematopoietic Cell
  • Journal Title: J Hematol Oncol Volume: 8 Pages: 102
  • DOI: 10.1186/s13045-015-0201-x
  • Peer Reviewed
• [Presentation] A Comparison of the Outcomes of Autologous and UnrelatedDonor Transplantation in Adult IntermediateRisk Acute Myeloid Leukemia Patients in First Complete Remission (2016)
  • Author(s): Motonori Mizutani, Akiyoshi Takami, Masahiko Hara, Shohei Mizuno, Masamitsu Yanada, Kazuteru Ohashi, Kensuke Usuki, Hitoji Uchiyama, Takaaki Chou, Toshihiro Miyamoto, Junji Tanaka, Yoshiko Atsuta and Shingo Yano
  • Organizer: 2016 BMT Tandem Meetings
  • Place of Presentation: ホノルル（ハワイコンベンションセンター）
  • Year and Date: 2016-02-18 – 2016-02-22
  • Int'l Joint Research
• [Presentation] Outcome and Risk Factors for Therapy-Related Myeloid Neoplasms Treated with Allogeneic Stem Cell Transplantation. (2015)
  • Author(s): Kida M, Usuki K, Uchida N, Fukuda T, Iwato K, Matsuoka K-i, Eto T, Ichinohe T, Atsuta Y, Takanashi M, Takami A, Miyazaki Y, Yano S, Ishiyama K
  • Organizer: 57th American Society of Hematology Annual Meeting
  • Place of Presentation: 米国、オーランド
  • Year and Date: 2015-12-05 – 2015-12-08
  • Int'l Joint Research
• [Presentation] Efficacy of High-Dose Cytarabine Added to Cyclophosphamide/Total-Body Irradiation in the Conditioning Regimen of Allogeneic Hematopoietic Cell Transplantation for Myeloid Malignancy. (2015)
  • Author(s): Arai Y, Aoki K, Takeda J, Kondo T, Eto T, Ota S, Hashimoto H, Fukuda T, Ozawa Y, Kanda Y, Kato C, Kurokawa M, Iwato K, Onizuka M, Ichinohe T, Atsuta Y, Takami A
  • Organizer: 57th American Society of Hematology Annual Meeting
  • Place of Presentation: 米国、オーランド
  • Year and Date: 2015-12-05 – 2015-12-08
  • Int'l Joint Research
• [Presentation] Overexpression of Salivary-Type Amylase Reduces the Sensitivity to Bortezomib in Multiple Myeloma Cells (2015)
  • Author(s): Shohei Mizuno, Ichiro Hanamura, Akinobu Ota, Sivasundaram Karnan, Tomoko Narita, Masaki Ri, Mineaki Goto, Mayuko Gotou, Norikazu Tsunekawa, Masato Shikami, Shinsuke Iida, Yoshitaka Hosokawa, Hiroshi Miwa, Ryuzo Ueda, Nitta Masakazu, Akiyoshi Takami
  • Organizer: 20th Congress of European Hematology Association (EHA)
  • Place of Presentation: オーストリア ウィーン
  • Year and Date: 2015-06-11 – 2015-06-14
  • Int'l Joint Research