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

2016 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: 免疫調整遺伝子多型

Outline of Annual Research Achievements

臨床解析において、日本国内でマイナーアリル頻度が比較的高いTLRファミリーとCCR5各遺伝子多型に着目し、同種造血幹細胞移植における臨床的影響を検証した。TLR1、TLR4、CCR5の各遺伝子多型が同種造血幹細胞移植後転帰に影響することを初めて明らかにした。TLR4遺伝子多型について検証コホート研究を実施し、再現性を確認した。TLR4高発現が予想される遺伝子多型を有するドナーから移植を受けると致死性感染症が増えることが示唆された。TLR4は感染免疫に重要な役割を示すが、過剰発現は逆に臓器障害を助長する可能性を示唆している。今回の結果から、TLR4遺伝子多型解析は同種造血幹細胞移植におけるドナー選択の最適化に寄与すると考えられた。TLR4調整が、造血幹細胞移植後臓器障害の予防・改善にとどまらず、通常の敗血症関連臓器障害の新規治療戦略に役立つ可能性も示唆された。機能解析において、NKG2D遺伝子多型が血液がんへの造血幹細胞移植ドナー選択や移植後合併症予測に関連すること、NKG2DがmicroRNA-1245を通じNK活性を調整することを明らかにしてきた。このNKG2D遺伝子多型-microRNA-1245系が、NK活性や細胞傷害性の多寡や、パピローマウイルス関連癌の疾患感受性に関わっていることを初めて明らかにした。血液がんへの造血幹細胞移植免疫関連遺伝子多型解析を通じ、血液がんのみならず、固形腫瘍の疾患感受性が明らかになったことに価値と発展性がある。さらに、遺伝子多型がNK活性を調製する分子機序が明らかとなり、自己免疫疾患や感染症、臓器移植診療、新規がん治療法開発への波及効果も期待される。

Current Status of Research Progress

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

Reason

候補免疫調整遺伝子多型の臨床解析をほぼ予定通り実施できた。機能解析も進めている。前向き研究も開始した。学会発表、論文投稿も行っており、おおむね順調に進展していると判断した。ただし、精密医療の探索や機能解析を終えるまでには至らず、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

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、分子機序の解明を図る。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。

Research Products

• [Journal Article] Toll-like receptor genetic variations in bone marrow transplantation (2017)
  • Author(s): Uchino, K., Mizuno, S., Sato-Otsubo, A., Nannya, Y., Mizutani, M., Horio, T., Hanamura, I., Espinoza, J. L., Onizuka, M., Kashiwase, K., Morishima, Y., Fukuda, T., Kodera, Y., Doki, N., Miyamura, K., Mori, T., Ogawa, S. and Takami, A.
  • Journal Title: Oncotarget Volume: 8 Pages: 45670-45686
  • DOI: 10.18632/oncotarget.17315
  • Peer Reviewed
• [Journal Article] The simultaneous inhibition of the mTOR and MAPK pathways with Gnetin-C induces apoptosis in acute myeloid leukemia (2017)
  • Author(s): Espinoza, J. Luis, Elbadry, Mahmoud I., Taniwaki, Masafumi, Harada, Kenichi, Trung, Ly Quoc, Nakagawa, Noriharu, Takami, Akiyoshi, Ishiyama, Ken, Yamauchi, Takuji, Takenaka, Katsuto and Nakao, Shinji
  • Journal Title: Cancer Letters Volume: 397 Pages: 1-12
  • DOI: 10.1016/j.canlet.2017.04.027
  • Peer Reviewed / Open Access
• [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] Toll-like receptor 1 variation increases the risk of transplant-related mortality in hematologic malignancies (2016)
  • Author(s): Uchino, K., Mizuno, S., Mizutani, M., Horio, T., Hanamura, I., Espinoza, J. L., Matsuo, K., Onizuka, M., Kashiwase, K., Morishima, Y., Fukuda, T., Kodera, Y., Doki, N., Miyamura, K., Mori, T. M., Takami, A. and Japan Marrow Donor, Program
  • Journal Title: Transpl Immunol Volume: 38 Pages: 60-6
  • DOI: 10.1016/j.trim.2016.06.002
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Fibroblast Growth Factor-2 facilitates the growth and chemo-resistance of leukemia cells in the bone marrow by modulating osteoblast functions (2016)
  • Author(s): Sugimoto, K., Miyata, Y., Nakayama, T., Saito, S., Suzuki, R., Hayakawa, F., Nishiwaki, S., Mizuno, H., Takeshita, K., Kato, H., Ueda, R., Takami, A. and Naoe, T.
  • Journal Title: Sci Rep Volume: 6 Pages: 30779
  • DOI: 10.1038/srep30779
  • Peer Reviewed / Open Access
• [Journal Article] Dietary phytochemicals and cancer chemoprevention: a review of the clinical evidence (2016)
  • Author(s): Kotecha, R., Takami, A. and Espinoza, J. L.
  • Journal Title: Oncotarget Volume: 7 Pages: 52517-52529
  • DOI: 10.18632/oncotarget.9593
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Acute megakaryoblastic leukemia, unlike acute erythroid leukemia, predicts an unfavorable outcome after allogeneic HSCT (2016)
  • Author(s): Ishiyama, K., Yamaguchi, T., Eto, T., Ohashi, K., Uchida, N., Kanamori, H., Fukuda, T., Miyamura, K., Inoue, Y., Taguchi, J., Mori, T., Iwato, K., Morishima, Y., Nagamura-Inoue, T., Atsuta, Y., Sakamaki, H. and Takami, A.
  • Journal Title: Leuk Res Volume: 47 Pages: 47-53
  • DOI: 10.1016/j.leukres.2016.04.017
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] A functional polymorphism in the NKG2D gene modulates NK-cell cytotoxicity and is associated with susceptibility to Human Papilloma Virus-related cancers (2016)
  • Author(s): Espinoza, J. L., Nguyen, V. H., Ichimura, H., Pham, T. T., Nguyen, C. H., Pham, T. V., Elbadry, M. I., Yoshioka, K., Tanaka, J., Trung, L. Q., Takami, A. and Nakao, S.
  • Journal Title: Sci Rep Volume: 6 Pages: 39231
  • DOI: 10.1038/srep39231
  • Peer Reviewed / Open Access / 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
• [Presentation] Establishment of a Novel DLBCL Cell Line: AMU-ML2, Derived from a Primary Refractory Patient Shows Homogeneous Staining Region of 8q24 Inducing High Expression of Long Non-Coding RNAs Encoded By PVT1 and Resistance to Vincristine (2016)
  • Author(s): Mizuno, S., Hanamura, I., Ota, A., Karnan, S., Uchino, K., Horio, T., Mizutani, M., Goto, M., Takahashi, M., Gotou, M., Hidesuke, Y., Watarai, M., Shikami, M., Hosokawa, Y., Miwa, H., Ueda, R., Nitta, M. and Takami, A.
  • Organizer: America Society of Hematology Annual Meeting
  • Place of Presentation: San Diego
  • Year and Date: 2016-12-03 – 2016-12-06
  • Int'l Joint Research
• [Presentation] Donor and Recipient Toll-Like Receptor 1 Variations Comparably Predict Transplant-Related Mortality after Unrelated Bone Marrow Transplantation (2016)
  • Author(s): Uchino, K., Mizuno, S., Mizutani, M., Horio, T., Hanamura, I., Espinoza, J. L., Matsuo, K., Onizuka, M., Kashiwase, K., Morishima, Y., Fukuda, T., Kodera, Y., Doki, N., Doki, N., Miyamura, K., Mori, T. and Takami, A.
  • Organizer: European Hematology Association Annual Meeting
  • Place of Presentation: Copenhagen
  • Year and Date: 2016-06-09 – 2016-06-12
  • Int'l Joint Research
• [Presentation] Recipient Ccr5 Genetic Variation Predicts Transplant Outcomes after Hla-Matched Unrelated Donor Bone Marrow Transplantation (2016)
  • Author(s): Horio, T., Mizuno, S., Mizutani, M., Uchino, K., Hanamura, I., Espinoza, J. L., Matsuo, K., Onizuka, M., Kashiwase, K., Morishima, Y., Fukuda, T., Kodera, Y., Doki, N., Miyamura, K., Takehiko, M. and Takami, A.
  • Organizer: European Hematology Association Annual Meeting
  • Place of Presentation: Copenhagen
  • Year and Date: 2016-06-09 – 2016-06-12
  • Int'l Joint Research