慢性骨髄性白血病幹細胞とT315I変異クローンの根絶

2011 Fiscal Year Annual Research Report

• Project/Area Number: 21390293
• Research Institution: Kyoto University
• Principal Investigator: 前川 平 京都大学, 医学研究科, 教授 (80229286)
• Co-Investigator(Kenkyū-buntansha): 平位 秀世 京都大学, 医学研究科, 助教 (50315933) ; 三浦 康生 京都大学, 医学研究科, 助教 (70605146) ; 芦原 英司 京都府立医科大学, 医学研究科, 講師 (70275197)
• Keywords: 慢性骨髄白血病 / 低酸素 / 幹細胞

Research Abstract

本研究の目的は、慢性骨髄性白血病(Chronic Myeloid Leukemia ; CML)を完治させるためにイマチニブの他、ダサチニブ、ニロチニブなどの第二世代のABLチロシンキナーゼ阻害剤(TKI)に残されたふたつの課題、(1)CML幹細胞を殲滅する戦略、および(2)T315I変異(ABLキナーゼドメインの315番目のスレオニンがイソロイシンに変異)にも有効な治療法を開発することにあった。
(1)CML幹細胞職滅戦略
イマチニブやその効果を高めた第二世代TKIのダサチニブ、ニロチニブ、それにわれわれが開発したバフェチニブをもってしてもCML幹細胞を根絶することは困難であった。CML幹細胞は低酸素環境にある骨髄ニッチに潜むと考えられる。通常の抗がん剤や分子標的治療薬は低酸素状態で活性が低下するが、われわれは放線菌から分離したRakicidinAが低酸素状態選択的に抗白血病活性を示すことを明らかにした(Cancer Sci, 2011)。
(2)T315I変異の克服
イマチニブや第二世代TKIはいずれもT3151変異を持つBCR/ABLを有する症例には無効である。我々はこのT315I変異症例にも有効なオーロラキナーゼ阻害剤AT9283を開発した。さらに、CML幹細胞の増殖にWnt/β-cateninシグナルが重要な働きをしていることから、Wnt/β-catenin阻害剤AV65がT315変異をもつCML症例にも有効であることを示した(Cancer Lett.2011).

Research Products

• [Journal Article] Rapid automated detection of ABL kinase domain mutations in imatinib-resistant patients (2011)
  • Author(s): Tanaka, R., Kimura, S., Ashihara, E., Yoshimura, M., Takahashi, N., Wakita, H., Itoh, K., Nishiwaki, K., Suzuki, K., Nagao, R., Yao, H., Hayashi, Y., Satake, S., Hirai, H., Sawada, K-I., Ottmann, O. G., Melo, J. V.
  • Journal Title: Cancer Letter Volume: 312(2) Pages: 228-34
  • DOI: doi:10.1016/j.canlet.2011.08.009
• [Journal Article] Phase I/II a clinical trials of dendritic cell-based immunotherapy for acute myeloid leukemia in elderly patients using autologous apoptotic leukemic cells or a heteroclitic WT1 peptide as antigens (2011)
  • Author(s): Kitawaki T, Kadowaki, T, Maekawa T, et al
  • Journal Title: Brit J Haematol Volume: 153 Pages: 796-799
  • DOI: 10.1111/j.1365-2141.2010.08490.x
  • Peer Reviewed
• [Journal Article] AV-65, a novel Wnt/β-catenin signal inhibitor, successfully suppresses progression of multiple myeloma in a mouse model (2011)
  • Author(s): Yao H, Ashihara E, Maekawa T, et al
  • Journal Title: Blood Cancer Journal Volume: 1 Pages: e43
  • DOI: 10.1038/bcj.2011.41
  • Peer Reviewed
• [Journal Article] Galectin-3 induced by leukemia microenvironment promotes drug resistance and bone marrow lodgment in chronic myelogenous leukemia (2011)
  • Author(s): Yamamoto-Sugitani M, Kuroda J, Maekawa T, et al
  • Journal Title: Proc Natl Acad Sci USA Volume: 108 Pages: 17468-17473
  • DOI: 10.1073/pnas.1111138108
  • Peer Reviewed
• [Journal Article] Growth inhibition of imatinib-resistant CML cells with the T315I mutation and hypoxia-adaptation by AV65, a novel Wnt/β-catenin signaling inhibitor (2011)
  • Author(s): Nagao R, Ashihara E, Maekawa T, et al
  • Journal Title: Cancer Lett Volume: 312 Pages: 91-100
  • DOI: 10.1016/j.canlet.2011.08.002
  • Peer Reviewed
• [Journal Article] Rakicidin A effectively induces apoptosis in hypoxia adapted Bcr-Abl positive leukemic cells (2011)
  • Author(s): Takeuchi M, Ashihara E, Maekawa T, et al
  • Journal Title: Cancer Sci Volume: 102 Pages: 591-6
  • DOI: 10.1111/j.1349-7006.2010.01813.x
  • Peer Reviewed
• [Journal Article] Galection-9 ameliorates acute Graft-versus-host disease through the induction of T-cell apoptosis (2011)
  • Author(s): Sakai K, Ashihara E, Maekawa T, et al
  • Journal Title: Eur J Immunol Volume: 41 Pages: 67-75
  • DOI: 10.1002/eji.200939931
  • Peer Reviewed
• [Journal Article] Cross-priming of CD8(+) T cells in vivo by dendritic cells pulsed with autologo us apoptotic leuke mic cells in immunotherapy for elderly patients with acute myeloid leukemia (2011)
  • Author(s): Kitawaki T, Kadowaki, T,Maekawa T, et al
  • Journal Title: Exp Hematol Volume: 39 Pages: 424-433.e2
  • DOI: 10.1016/j.exphem.2011.01.001
  • Peer Reviewed
• [Journal Article] Targeting the Wnt/β-catenin signaling pathway in human cancers (2011)
  • Author(s): Yao H, Ashihara E, Maekawa T
  • Journal Title: Expert Opinion on Therapeutic Targets Volume: 15 Pages: 873-887
  • DOI: 10.1517/14728222.2011.577418
  • Peer Reviewed
• [Journal Article] RNA interference against Polo-like kinase-1 in advanced non-small cell lung cancers (2011)
  • Author(s): Kawata E, Ashihara E, Maekawa T
  • Journal Title: J Clin Bioinformatics Volume: 1 Pages: 6
  • DOI: 10.1186/2043-9113-1-6
  • Peer Reviewed
• [Presentation] A microfluidic device to mimic the bone marrow environment : real-time observation of the leukemic cell behavior (2011)
  • Author(s): Munaka T, Ashihara E, Maekawa T, et al
  • Organizer: The 15^<th> International Conference on Miniaturized Systems for Chemistry and Life Sciences
  • Place of Presentation: 米国、シアトル
  • Year and Date: 20111002-20111006
• [Presentation] BCR/ABL-mediated myeloid expresion is promoted by C/EBPβ, a regulator of emergency granulopoiesis (2011)
  • Author(s): Hayashi Y, Hirai H, Maekawa T, et al
  • Organizer: 第53回アメリカ血液学会
  • Place of Presentation: 米国、サンディエゴ
  • Year and Date: 2011-12-12
• [Presentation] Parathyroid hormone stimulates human mesenchymal stem cells to enhance the expansion of hematopoietic stem cells (2011)
  • Author(s): Yao H, Miura Y, Maekawa T, et al
  • Organizer: 第53回アメリカ血液学会
  • Place of Presentation: 米国、サンディエゴ
  • Year and Date: 2011-12-11
• [Presentation] Combined effects of a pan-Abl1 kinase inhibitor, ponatinib and dasatinib against T315I mutant forms of Bcr-Abl1 : in vitro and in vivo studies (2011)
  • Author(s): Tauchi T, Maekawa T, Ohyashiki K, et al
  • Organizer: 第53回アメリカ血液学会
  • Place of Presentation: 米国、サンディエゴ
  • Year and Date: 2011-12-11
• [Presentation] Targeting the hedgehog signaling pathway in therapy-resistant Bcr-Abl1 positive leukemia with ponatinib (2011)
  • Author(s): Katagiri S, Maekawa T, Ohyashiki K, et al
  • Organizer: 第53回アメリカ血液学会
  • Place of Presentation: 米国、サンディエゴ
  • Year and Date: 2011-12-11
• [Presentation] Combined effects of the hedgehog inhibitor LDE225 and nilotinib in a random mutagesesis screen (2011)
  • Author(s): Tauchi T, Okabe S, Maekawa T, et al
  • Organizer: 第73回日本血液学会総会
  • Place of Presentation: 名古屋国際会議場(愛知県)
  • Year and Date: 2011-10-15
• [Presentation] Involvement of C/EBPβ in BCR/ABL-dependent leukemogenesis (2011)
  • Author(s): Hayashi Y, Hirai H, Maekawa T, et al
  • Organizer: 第73回日本血液学会学術集会
  • Place of Presentation: 名古屋国際会議場(愛知県)
  • Year and Date: 2011-10-15
• [Presentation] Cord blood transplantation for T3151-mutated blastic-phase chronic myeloid leukemia (2011)
  • Author(s): Kunitomi A, Kotani S, Maekawa T, et al
  • Organizer: 第73回日本血液学会学術集会
  • Place of Presentation: 名古屋国際会議場(愛知県)
  • Year and Date: 2011-10-15
• [Presentation] A new BCR/ABL-positive megakaryoblastic cell line resistant to both imatinib and dasatinib (2011)
  • Author(s): Shimazu Y, Hishizawa M, Maekawa T, et al
  • Organizer: 第73回日本血液学会学術集会
  • Place of Presentation: 名古屋国際会議場(愛知県)
  • Year and Date: 2011-10-14
• [Presentation] Galectin-3 induced by leukemia microenvironment promotes drug resistance and BM lodgment in CML (2011)
  • Author(s): Yamamoto M, Kuroda J, Maekawa T, et al
  • Organizer: 第73回日本血液学会学術集会
  • Place of Presentation: 名古屋国際会議場(愛知県)
  • Year and Date: 2011-10-14
• [Presentation] AV-65 inhibited the growth of myeloma cells by enhancing β-TrCP-mediated β-catenin ubiquitination (2011)
  • Author(s): Yao H, Ashihara E, Maekawa T, et al
  • Organizer: 第73回日本血液学会学術集会
  • Place of Presentation: 名古屋国際会議場(愛知県)
  • Year and Date: 2011-10-14
• [Remarks]
  • URL: http://dtm.kuhp.kyoto-u.ac.jp/
• [Remarks]
  • URL: http://www.kuhp.kyoto-u.ac.jp/~ccmt/