白血病幹細胞特異的抗原ＴＩＭ―３に対する標的治療の開発

2014 Fiscal Year Annual Research Report

• Project/Area Number: 23390254
• Research Institution: Kyushu University
• Principal Investigator: 宮本 敏浩 九州大学, 大学病院, 講師 (70343324)
• Co-Investigator(Kenkyū-buntansha): 赤司 浩一 九州大学, 医学(系)研究科(研究院), 教授 (80380385)
• Project Period (FY): 2011-04-01 – 2015-03-31
• Keywords: 白血病 / 幹細胞 / TIM-3 / 標的治療

Outline of Annual Research Achievements

申請者らは先行研究において、ヒト急性骨髄性白血病(AML)における癌幹細胞であるCD34+CD38-白血病幹細胞とCD34+CD38-ヒト正常造血幹細胞を純化し、マイクロアレイによる網羅的遺伝子発現解析を行った。その結果、T-cell immunoglobulin mucin-3 (TIM-3)が、正常造血幹細胞には発現せずに、白血病幹細胞に特異的に高発現していることを報告した（Kikushige et al., Cell Stem Cell, 2010）。本研究において、申請者らはTIM-3を標的とした治療戦略を開発するうえで、その機能解明が重要であると考え、ヒト白血病幹細胞におけるTIM-3の機能解析を行った。TIM-3リガンドであるgalectin-9およびHMGB-1に注目し、TIM-3リガンドによる刺激後の白血病幹細胞の網羅的遺伝子発現変化を評価したところ、galectin-9が特徴的遺伝子発現変化をもたらすことを見いだした。そこで、まずgalectin-9に着目して研究をすすめた。ヒトgalectin-9の生理的血中濃度を明らかにするために、健常人および造血器腫瘍患者血清中のgalectin-9濃度をELISA法により測定した。その結果、急性骨髄性白血病患者では、galectin-9の血中濃度が上昇していることを見いだし、その機序として白血病細胞自身がgalectin-9を産生、分泌していることを明らかにした。また、その下流のシグナル経路の同定を行い、TIM-3の機能として自己複製能を含む幹細胞活性に関連していることを見いだした。

Research Progress Status

26年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

26年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] A Single high-resolution HLA mismatch has a similar adverse impact on the outcome of related hematopoietic stem cell transplantation as a single low-resolution HLA mismatch. (2015)
  • Author(s): Fuji S, Kanda J, Kato S, Ikegame K, Morishima S, Miyamoto T, Hidaka M, Kubo K, Miyamura K, Tsudo M, Kobayashi H, Maesako Y, Eto T, Adachi S, Ichinohe T, Atsuta Y, Kanda Y.
  • Journal Title: Am J Hematol Volume: 未定 Pages: 未定
  • DOI: 10.1002/ajh.24028
  • Peer Reviewed
• [Journal Article] α-Mannan induces Th17-mediated pulmonary graft-versus-host disease in mice. (2015)
  • Author(s): Uryu H, Hashimoto D, Kato K, Hayase E, Matsuoka S, Ogasawara R, Takahashi S, Maeda Y, Iwasaki H, Miyamoto T, Saijo S, Iwakura Y, Hill GR, Akashi K, Teshima T
  • Journal Title: Blood Volume: 未定 Pages: 未定
  • Peer Reviewed
• [Journal Article] Dose-intensified chemotherapy alone or in combination with mogamulizumab in newly diagnosed aggressive adult T-cell leukaemia-lymphoma: a randomized phase II study. (2015)
  • Author(s): Ishida T, Jo T, Takemoto S, Suzushima H, Uozumi K, Yamamoto K, Uike N, Saburi Y, Nosaka K, Utsunomiya A, Tobinai K, Fujiwara H, Ishitsuka K, Yoshida S, Taira N, Moriuchi Y, Imada K, Miyamoto T, Akinaga S, Tomonaga M, Ueda R
  • Journal Title: Br J Haematol Volume: 未定 Pages: 未定
  • DOI: 10.1111/bjh.13338.
  • Peer Reviewed
• [Journal Article] Factors prognostic of eligibility for allogeneic HCT among older patients with AML-CR1 and adverse- or intermediate-risk cytogenetics. (2015)
  • Author(s): Yamasaki S, Yoshimoto G, Ogawa R, Aoki K, Higuchi M, Harada N, Arima F, Kondo S, Matubara F, Takahashi T, Uike N, Miyamoto T, Okamura S, Akashi K; for the Fukuoka Blood and Marrow Transplantation Group
  • Journal Title: Ann Hematol Volume: 未定 Pages: 未定
  • Peer Reviewed
• [Journal Article] Pre-malignant lymphoid cells arise from hematopoietic stem/progenitor cells in chronic lymphocytic leukemia. (2015)
  • Author(s): Kikushige Y, Miyamoto T
  • Journal Title: Int J Hematol Volume: 未定 Pages: 未定
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] CD41 marks the initial myelo-erythroid lineage specification in adult mouse hematopoiesis: redefinition of murine common myeloid progenitor. (2015)
  • Author(s): Miyawaki K, Arinobu Y, Iwasaki H, Kohno K, Tsuzuki H, Iino T, Shima T, Kikushige Y, Takenaka K, Miyamoto T, Akashi K.
  • Journal Title: Stem Cells Volume: 33 Pages: 976-987
  • DOI: 10.1002/stem.1906.
  • Peer Reviewed
• [Journal Article] Characteristics of patients with development of large granular lymphocyte expansion among dasatinib-treated patients with relapsed Philadelphia chromosome-positive acute lymphoblastic leukemia after allogeneic stem cell transplantation. (2015)
  • Author(s): Ito Y, Miyamoto T, Kamimura T, Aoki K, Henzan H, Aoki T, Shiratsuchi M, Kato K, Nagafuji K, Ogawa R, Eto T, Iwasaki H, Akashi K.
  • Journal Title: Clin Lymphoma Myeloma Leuk. Volume: 15 Pages: 47-54
  • DOI: 10.1016/j.clml.2014.09.006
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Impact of HLA allele mismatch on the clinical outcome in serologically matched related hematopoietic SCT. (2014)
  • Author(s): Fuji S, Kanda J, Kato S, Ikegame K, Morishima S, Miyamoto T, Hidaka M, Kubo K, Miyamura K, Ohashi K, Kobayashi H, Maesako Y, Adachi S, Ichinohe T, Atsuta Y, Kanda Y; HLA Working Group of Japan Society for Hematopoietic Cell Transplantation.
  • Journal Title: Bone Marrow Transplant Volume: 49 Pages: 1187-1192
  • DOI: 10.1038/bmt.2014.141.
  • Peer Reviewed
• [Journal Article] Combination of bortezomib, thalidomide, and dexamethasone (VTD) as a consolidation therapy after autologous stem cell transplantation for symptomatic multiple myeloma in Japanese patients. (2014)
  • Author(s): Takashima S, Miyamoto T, Kadowaki M, Ito Y, Aoki T, Takase K, Shima T, Yoshimoto G, Kato K, Muta T, Shiratsuchi M, Takenaka K, Iwasaki H, Teshima T, Kamimura T, Akashi K.
  • Journal Title: Int J Hematol Volume: 100 Pages: 159-164
  • DOI: 10.1007/s12185-014-1611-1
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Multicenter phase II study of mogamulizumab (KW-0761), a defucosylated anti-cc chemokine receptor 4 antibody, in patients with relapsed peripheral T-cell lymphoma and cutaneous T-cell lymphoma. (2014)
  • Author(s): Ogura M, Ishida T, Hatake K, Taniwaki M, Ando K, Tobinai K, Fujimoto K, Yamamoto K, Miyamoto T, Uike N, Tanimoto M, Tsukasaki K, Ishizawa K, Suzumiya J, Inagaki H, Tamura K, Akinaga S, Tomonaga M, Ueda R.
  • Journal Title: J Clin Oncol Volume: 32 Pages: 1157-1163
  • DOI: 10.1200/JCO.2013.52.0924
  • Peer Reviewed
• [Journal Article] The BALB/c-specific polymorphic SIRPA enhances its affinity for human CD47, inhibiting phagocytosis against human cells to promote xenogeneic engraftment. (2014)
  • Author(s): Iwamoto C, Takenaka K, Urata S, Yamauchi T, Shima T, Kuriyama T, Daitoku S, Saito Y, Miyamoto T, Iwasaki H, Kitabayashi I, Itoh K, Kishimoto J, Kohda D, Matozaki T, Akashi K.
  • Journal Title: Exp Hematol Volume: 42 Pages: 163-171
  • DOI: 10.1016/j.exphem.2013.11.005.
  • Peer Reviewed
• [Journal Article] Expansion of donor-reactive host T cells in primary graft failure after allogeneic hematopoietic SCT following reduced-intensity conditioning. (2014)
  • Author(s): Koyama M, Hashimoto D, Nagafuji K, Eto T, Ohno Y, Aoyama K, Iwasaki H, Miyamoto T, Hill GR, Akashi K, Teshima T.
  • Journal Title: Bone Marrow Transplant. Volume: 2014 Pages: 110-115
  • DOI: 10.1038/bmt.2013.134.
  • Peer Reviewed
• [Journal Article] The ordered acquisition of Class II and Class I mutations directs formation of human t(8;21) acute myelogenous leukemia stem cell. (2014)
  • Author(s): Shima T, Miyamoto T, Kikushige Y, Yuda J, Tochigi T, Yoshimoto G, Kato K, Takenaka K, Iwasaki H, Mizuno S, Goto N, Akashi K.
  • Journal Title: Exp Hematol Volume: 42 Pages: 955-965
  • DOI: 10.1016/j.exphem.2014.07.267.
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] 造血器腫瘍における治療選択と臨床検査 (2014)
  • Author(s): 宮本敏浩
  • Organizer: 日本臨床検査医学会学術集会
  • Place of Presentation: 福岡市
  • Year and Date: 2014-11-25 – 2014-11-25
  • Invited
• [Presentation] 骨髄増殖性腫瘍の治療 (2014)
  • Author(s): 宮本敏浩
  • Organizer: 日本血液学会総会
  • Place of Presentation: 大阪市
  • Year and Date: 2014-11-02 – 2014-11-02
  • Invited
• [Presentation] 高齢者造血器腫瘍に対する最新の治療 (2014)
  • Author(s): 宮本敏浩
  • Organizer: 日本老年医学学会
  • Place of Presentation: 福岡市
  • Year and Date: 2014-06-14 – 2014-06-14
  • Invited
• [Book] 血液疾患最新の治療 (2014)
  • Author(s): 吉本五一、宮本敏浩
  • Total Pages: 10
  • Publisher: 南江堂
• [Remarks] 九州大学第一内科ホームページ
  • URL: http://www.1nai.med.kyushu-u.ac.jp