造血幹細胞ニッチを標的とした新規白血病治療法の開発

2013 Fiscal Year Annual Research Report

• Project/Area Number: 24390248
• Research Institution: Tokai University
• Principal Investigator: 安藤 潔 東海大学, 医学部, 教授 (70176014)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Keywords: 白血病幹細胞 / ニッチ / PAI-1

Research Abstract

本研究は白血病幹細胞のニッチを標的とした新規治療法を開発することを目的としている。申請者らは放射線照射後あるいは抗癌剤投与後に骨髄ニッチ領域にplasminogen activator inhibitor-1 (PAI-1)が誘導されることを見出し、われわれが開発したPAI-1阻害剤（TM5275）を投与すると造血幹細胞がニッチより離脱して細胞周期に入ることを確認している。この作用をニッチに存在し治療抵抗性である白血病幹細胞の治療に応用する。具体的には研究期間内に、１）TM5275によるニッチ構成細胞における遺伝子発現変化を解析する、２）マウス白血病モデルでTM5275の至適投与法を検討する、３）ヒト白血病および骨髄異形成症候群モデルマウスでTM5275を併用した新規治療法を開発する。本年度は化合物投与により造血幹細胞が枯渇しないことをマウス実験系を用いて確認した。また、bcr-abl遺伝子導入マウス細胞を用いて本剤の治療効果を確認した。

Current Status of Research Progress

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

Reason

当初の計画通り研究を推進した。

Strategy for Future Research Activity

ヒト慢性骨髄性白血病細胞株であるK562をNOGマウスに移植し、ヒト細胞での治療効果を確認する。

Expenditure Plans for the Next FY Research Funding

新年度早々に購入予定の抗体が生じたため
human CD138を購入予定

Research Products

• [Journal Article] Inhibition of plasminogen activator inhibitor type-1 activity enhances rapid and sustainable hematopoietic regeneration. (2014)
  • Author(s): Ibrahim AA, Yahata T, Onizuka M, Dan T, Van Ypersele De Strihou C, Miyata T, Ando K
  • Journal Title: Stem Cells, Volume: 32 Pages: 959-973
  • DOI: 10.1002
  • Peer Reviewed
• [Journal Article] Deferasirox treatment improved hematopoiesis and led to complete remission in a patient with pure red cell aplasia. (2013)
  • Author(s): Kojima M, Machida S, Miyamoto M, Moriuchi M, Ohbayash Y, Ando K.
  • Journal Title: Int J Hematol. Volume: 98 Pages: 719-722
  • Peer Reviewed
• [Journal Article] Phase I study of intravenous low-dose granulocyte-colony stimulating factor in acute and sub-acute ischemic stroke. (2013)
  • Author(s): Moriya Y, Mizuma A, Uesugi T, Ohnuki Y, Nagata E, Takahashi W, Kobayashi H, Kawada H, Ando K, Takagi S, Takizawa S.
  • Journal Title: Journal of Stroke and Cerebrovascular Diseases Volume: 22 Pages: 1088-1097
  • Peer Reviewed
• [Journal Article] A phase I/II study of VMP (bortezomib-melphalan-prednisolone) for previously untreated patients with multiple myeloma in Japan. (2013)
  • Author(s): Ogawa Y, Suzuki K, Sakai A, Iida S, Ogura M, Tobinai KOgawa Y, Suzuki K, Sakai A, Iida S, Ogura M, Tobinai K,, Matsumoto M, Matsue K, Terui Y, Ohashi K, Ishii M, Mukai H, Ando K, Hotta T
  • Journal Title: Cancer Sci Volume: 104 Pages: 912-919
  • Peer Reviewed
• [Journal Article] Multicenter Phase II Study of Bendamustine Plus Rituximab in Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma. (2013)
  • Author(s): Ohmachi K, Niitsu N, Uchida T, Kim SJ, Ando K, Takahashi N, Takahashi N, Uike N, Eom HS, Chae YS, Terauchi T, Tateishi U, Tatsumi M, Kim WS, Tobinai K, Suh C, Ogura M.
  • Journal Title: J Clin Oncol. Volume: 31 Pages: 2103-2109
  • Peer Reviewed
• [Journal Article] Stage I findings of a two-stage Phase II study to assess the efficacy, safety and tolerability of barasertib (AZD1152) compared with low dose cytosine arabinoside in elderly patients with acute myeloid leukemia. (2013)
  • Author(s): Kantarjian H, Martinelli G, Jabbour E, QuintAas-Cardama A, Ando K, Bay J-O, Wei A, Grvpper S, Papayannidis C, Owen K, Pike L, Schmitt N, Stockman P, Giagounidis A,
  • Journal Title: Cancer Volume: 119 Pages: 2611-2619
  • Peer Reviewed
• [Journal Article] High concentrations of L-ascorbic acid specifically inhibit the growth of human leukemic cells via downregulation of HIF-1Fa transcription (2013)
  • Author(s): Kawada H, Kaneko M, Sawanobori M, Uno T, Matsuzawa H, Nakamura Y, Matsushita H, Ando K.
  • Journal Title: PLOS ONE Volume: 8:e62717 Pages: 62717
  • Peer Reviewed
• [Journal Article] RUNX1/AML1 mutant collaborates with BMI1 overexpression in the development of human and murine myelodysplastic syndromes. (2013)
  • Author(s): Harada Y, Inoue D, Ding Y, Imagawa J, Doki N, Matsui H, Yahata T, Matsushita H, Ando K, Sashida G, Iwama A, Kitamura T, and Harada H
  • Journal Title: Blood Volume: 121 Pages: 3434-3446
  • Peer Reviewed
• [Journal Article] Scanning of the immunogenome with microsatellite markers for non-HLA associations with graft-versus-host disease in haematopoietic stem cell transplantation. (2013)
  • Author(s): Harkensee C, Oka A, Onizuka M, Middleton PG, Inoko H, Nakaoka H, Gennery AR, Ando K and Morishima Y.
  • Journal Title: Immunogenetics Volume: 65 Pages: 417-427
  • Peer Reviewed
• [Journal Article] MYC rearrangements are useful for predicting outcomes following rituximab and chemotherapy: multi-center analysis of Japanese patients with diffuse large B-cell lymphoma. (2013)
  • Author(s): Kojima M, Nishikii H, Takizawa J, Aoki S, Noguchi M, Chiba S, Ando K, and Nakamura N.
  • Journal Title: Leuk. Lymphoma Volume: 54 Pages: 2149-2154
  • Peer Reviewed