Functional analysis of genetic polymorphism associated with hematopoietic stem cell transplantation, and exploration for genome target therapy

• Project/Area Number: 15K09513
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Aichi Medical University
• Principal Investigator: Takami Akiyoshi 愛知医科大学, 医学部, 教授 (80324078)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 造血幹細胞移植 / 遺伝子多型 / 免疫調整遺伝子多型 / 一塩基多型

Outline of Final Research Achievements

The immunomodulation-related gene polymorphism analysis of patients who received allogeneic bone marrow transplantation and their donor showed that the polymorphic sites of functional genes with clinical significance, including NKG 2D, CXCL10, NLRP 3, THBD/BDCA3, TLR1, TLR4, CCL2, were concentrated in the 5’-untranslated region. It was also revealed that miRNA-1245 binds to the polymorphic site of the 5’-untranslated region of the activated NK receptor gene NKG2D, leading to suppress NK activity, and that miRNA-1245 in serum exosomes obtained from patients with hematologic malignancies is increased. Moreover, the binding ability of miRNA-1245 with the low NK cytotoxicity genotype was superior to that with the high NK cytotoxicity genotype.

Research Products

• [Journal Article] Hematopoietic stem cell transplantation for acute myeloid leukemia (2018)
  • Author(s): Takami, A
  • Journal Title: Int J Hematol Volume: 107 Issue: 5 Pages: 513-518
  • DOI: 10.1007/s12185-018-2412-8
  • Peer Reviewed
• [Journal Article] Decreased platelet count in children with epilepsy treated with valproate and its relationship to the immature platelet fraction (2018)
  • Author(s): Kurahashi, H., Takami, A., Murotani, K., Numoto, S. and Okumura, A.
  • Journal Title: Int J Hematol Volume: 107 Issue: 1 Pages: 105-111
  • DOI: 10.1007/s12185-017-2323-0
  • Peer Reviewed
• [Journal Article] Autologous hematopoietic cell transplantation for acute promyelocytic leukemia in second complete remission: outcomes before and after the introduction of arsenic trioxide (2017)
  • Author(s): Yanada M, Yano S, Kanamori H, Gotoh M, Emi N, Watakabe K, Kurokawa M, Nishikawa A, Mori T, Tomita N, Murata M, Hashimoto H, Henzan H, Kanda Y, Sawa M, Kohno A, Atsuta Y, Ichinohe T, Takami A
  • Journal Title: Leuk Lymphoma Volume: 58 Issue: 5 Pages: 1061-1067
  • DOI: 10.1080/10428194.2016.1231406
  • Peer Reviewed
• [Journal Article] Role of reduced-intensity conditioning allogeneic hematopoietic cell transplantation in older patients with de novo acute myeloid leukemia. (2017)
  • Author(s): Yamasaki S, Hirakawa A, Aoki J, Uchida N, Fukuda T, Ogawa H, Ohashi K, Kondo T, Eto T, Kanamori H, Okumura H, Iwato K, Ichinohe T, Kanda J, Onizuka M, Kuwatsuka Y, Yanada M, Atsuta Y, Takami A, Yano S.
  • Journal Title: Ann Hematol Volume: 96 Issue: 2 Pages: 289-297
  • DOI: 10.1007/s00277-016-2872-y
  • Peer Reviewed
• [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., Takami A.
  • Journal Title: Oncotarget Volume: 8 Issue: 28 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 JL, Elbadry MI, Taniwaki M, Harada K, Trung LQ, Nakagawa N, Takami A, Ishiyama K, Yamauchi T, Takenaka K, Nakao S
  • Journal Title: Cancer Lett Volume: 400 Pages: 127-136
  • 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, Kato H.
  • Journal Title: Transfusion Volume: 未定 Issue: 5 Pages: 1242-3
  • DOI: 10.1111/trf.13507
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Comparable outcomes between autologous and allogeneic transplant for adult acute myeloid leukemia in first complete remission. (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, Takami A.
  • Journal Title: BMT (in press) Volume: NA Issue: 5 Pages: 645-53
  • DOI: 10.1038/bmt.2015.349
  • Peer Reviewed
• [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, Naoe T
  • Journal Title: Scientific Reports Volume: 6 Issue: 1 Pages: 30779-30781
  • DOI: 10.1038/srep30779
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [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 Issue: 32 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
  • NAID: 120005830648
  • 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 JL, Nguyen VH, Ichimura H, Pham TT, Nguyen CH, Pham TV, Elbadry MI, Yoshioka K, Tanaka J, Trung LQ, Takami A, Nakao S
  • Journal Title: Sci Rep Volume: 6 Issue: 1 Pages: 39231-39231
  • DOI: 10.1038/srep39231
  • Peer Reviewed / Open Access
• [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, Ichinohe T, Atsuta Y, Yano S, Takami A
  • Journal Title: Bone Marrow Transplantation Volume: 51 Issue: 4 Pages: 604-606
  • DOI: 10.1038/bmt.2015.297
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [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，Takami A
  • Journal Title: Am J Hematol Volume: 91 Issue: 3 Pages: 302-307
  • 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 Issue: 3 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 Issue: 3 Pages: 278-287
  • 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 JL, Trung LQ, Takami A, Kondo Y, An DT, Sasaki M, Wakayama T, Nakao S.
  • Journal Title: PloS One Volume: - Issue: 4 Pages: e0120709-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 Issue: 4 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 Issue: 2 Pages: 295-300
  • 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 Issue: 5 Pages: 569-78
  • DOI: 10.1007/s12185-015-1859-0
  • Peer Reviewed / Int'l Joint Research
• [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 Issue: 9 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: Journal of Clinical and Experimental Hematopathology Volume: 55 Issue: 2 Pages: 89-96
  • DOI: 10.3960/jslrt.55.89
  • NAID: 130005104661
  • ISSN: 1346-4280, 1880-9952
  • 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 Issue: 6 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 Issue: 3 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 Issue: 1 Pages: 102-102
  • DOI: 10.1186/s13045-015-0201-x
  • NAID: 120005672589
  • Peer Reviewed
• [Journal Article] Increased glycosylphosphatidylinositol-anchored protein-deficient granulocytes define a benign subset of bone marrow failures in patients with trisomy 8. (2014)
  • Author(s): Hosokawa K, Sugimori N, Katagiri T, Sasaki Y, Saito C, Seiki Y, Mochizuki K, Yamazaki H, Takami A, Nakao S.
  • Journal Title: Eur J Haemat Volume: 18 Issue: 3 Pages: 230-238
  • DOI: 10.1111/ejh.12484
  • NAID: 120005661927
  • Peer Reviewed / Open Access
• [Presentation] A Higher Immature Platelet Fraction Predicts a Response to Corticosteroids in Adult Patients with Immune Thrombocytopenia (2017)
  • Author(s): Takami A
  • Organizer: International Society of Laboratory Hematology annual meeting
  • Int'l Joint Research
• [Presentation] Peripheral Blood Smear Tells: An Appraisal of the Howell-Jolly Bodies (2017)
  • Author(s): Nakagami Y, Takami A
  • Organizer: International Society of Laboratory Hematology annual meeting
  • Int'l Joint Research
• [Presentation] Single-Nucleotide Polymorphism in the Pbk Gene Is Closely Associated with Myeloma Cell Proliferation (2017)
  • Author(s): Hanamura I, Takami A
  • Organizer: European Hematology Association annual meeting
  • Int'l Joint Research
• [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
  • 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
  • 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
  • Int'l Joint Research
• [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
  • 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
  • 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
  • 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
  • Int'l Joint Research