白血病幹細胞を標的とした新規治療法確立のための基礎研究

• Project/Area Number: 10J00360
• Research Category: Grant-in-Aid for JSPS Fellows
• Allocation Type: Single-year Grants
• Section: 国内
• Research Field: Immunology
• Research Institution: Kochi University
• Principal Investigator: 西岡 千惠 高知大学, 医学部, 特別研究員PD
• Project Period (FY): 2010 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥2,800,000 (Direct Cost: ¥2,800,000); Fiscal Year 2012: ¥900,000 (Direct Cost: ¥900,000); Fiscal Year 2011: ¥900,000 (Direct Cost: ¥900,000); Fiscal Year 2010: ¥1,000,000 (Direct Cost: ¥1,000,000)
• Keywords: AML / leukemia stem cells / CD82 / STAT5 / MMP9 / 白血病幹細胞 / PTEN / p21

Research Abstract

我々は急性骨髄性白血病(AML)患者から採取した白血病幹細胞(CD34^+/CD38^-分画)に特異的に発現しているテトラスパニンCD82を同定し、このCD82の白血病幹細胞における機能解析に着手した結果、CD82が白血病幹細胞の骨髄内のニッチへの接着と生存に影響を及ぼしている可能性を見出した。またCD82が伝達する細胞内シグナルを探索するために、レンチウイラレス粒子を用いてcD82highの白血病細胞のcD82発現を低下させ、コントロールshRNAウイルス粒子を感染させた白血病細胞と、各種細胞内シグナル伝達蛋白質の発現レベルをウエスタンブロット法で定量化、比較検討した結果、CD82発現はSTAT5の活性と相関があり、同様のことがAML患者から採取したCD34^+/CD38^-細胞でも確認され、CD82がSTAT5を介して白血病幹細胞の生存も制御している可能性が示唆された。以上より、CD82は白血病幹細胞のニッチへの接着及びその生存を制御している可能性がある。ニッチベ接着した白血病幹細胞は抗がん剤に対して耐性を示すが、AML細胞表面上のCD82をブロックすればAML細胞の骨髄への接着が剥がされ、この剥がれたAML細胞を抗がん剤で駆逐可能かもしれないと期待される。そこでこのCD82の機能を阻害する目的でCD82モノクローナル抗体を使用して抗がん剤AraCとの併用効果を検討した。超免疫不全マウスにAML細胞を移植し、AML細胞の生着確認後これらの薬剤を投与、した結果、各単剤投与でも脾臓における白血病細胞の割合が低下したが、併用するとさらに低下した。これらの結果より、抗がん剤とCD82モノクローナル抗体の併用は白血病治療に有効である可能性が示唆された。

Research Products

• [Journal Article] CD34(+)/CD38(-) acute myelogenous leukemia cells aberrantly express CD82 which regulates adhesion and survival of leukemia stem cells. (2013)
  • Author(s): Nishioka C
  • Journal Title: Int J Cancer Volume: 132 Pages: 2006-2019
  • DOI: 10.1002/ijc.28277
  • Peer Reviewed
• [Journal Article] A novel treatment strategy targeting shugoshin 1 in hematological malignancies. (2013)
  • Author(s): Yang J
  • Journal Title: Leuk Res. Volume: 37 Issue: 1 Pages: 76-82
  • DOI: 10.1016/j.leukres.2012.10.002
  • Peer Reviewed
• [Journal Article] The combination of IκB kinase β inhibitor and everolimus modulates expression of inter leukin-10 in human T-cell lymphotropic virus type-1-infected T cells. (2013)
  • Author(s): Nishioka C
  • Journal Title: Immunology. Volume: 138 Issue: 3 Pages: 216-227
  • DOI: 10.1111/imm.12035
  • Peer Reviewed
• [Journal Article] Thrombomodulin enhances the anti-fibrinolytic and anti-leukemic effects of all-trans retinoic acid in acute promyelocytic leukemia cells (2012)
  • Author(s): Ikezoe T
  • Journal Title: Exp Hematol Volume: (In press)
  • Peer Reviewed
• [Journal Article] Thrombomodulin-induced differentiation of acute myelomonocytic leukemia cells via JNK signaling (2012)
  • Author(s): Yang J
  • Journal Title: Leuk Res Volume: (In press)
  • Peer Reviewed
• [Journal Article] Long-term exposure of gastrointestinal stromal tumor cells to sunitinib induces epigenetic silencing of the PTEN gene (2011)
  • Author(s): Yang J
  • Journal Title: Int J Cancer Volume: 130 Pages: 959-66
  • Peer Reviewed
• [Journal Article] Simultaneous inhibition of DNA methyltransferase and histone deacetylase induces p53-independent apoptosis via down-regulation of Mcl-1 in acute myelogenous leukemia cells (2011)
  • Author(s): Nishioka C
  • Journal Title: Leuk Res Volume: 35 Pages: 932-9
  • Peer Reviewed
• [Journal Article] Imatinib causes epigenetic alterations of PTEN gene via upregulation of DNA methyltransferases and polycomb group proteins (2011)
  • Author(s): Nishioka C
  • Journal Title: Blood Cancer Journal Volume: 1
  • Peer Reviewed
• [Journal Article] Inhibition of MEK/ERK signaling induces apoptosis of acutemyelogenous leukemi a cells via inhibition of eukaryotic initiation factor 4E-binding protein l and down-regulation of Mcl-1 (2010)
  • Author(s): Nishioka C
  • Journal Title: Apoptosis Volume: 15 Pages: 795-804
  • Peer Reviewed
• [Journal Article] Successful treatment of imatinib-resistant hypereosinophilic syndrome with nilotinib (2010)
  • Author(s): Ikezoe T
  • Journal Title: Leukemia Research Volume: 34
  • Peer Reviewed
• [Journal Article] Inhibition of mTORC1 by RADOOI (everolimus) potentiates the effects of 1, 25-dihydroxyvitamin D (3) to induce growth arrest and differentiation of AML cells in vitro and in vivo (2010)
  • Author(s): Yang J
  • Journal Title: Exp Hematol Volume: 38 Pages: 666-676
  • Peer Reviewed
• [Journal Article] Long-term exposure of leukemia cells to multi-targeted tyrosine kinase inhibitor induces activations of AKT, ERK and STAT5 signaling via epigenetic silencing of the PTEN gene (2010)
  • Author(s): Nishioka C
  • Journal Title: Leukemia Volume: 24 Pages: 1631-1640
  • Peer Reviewed
• [Journal Article] Inhibition of STAT5 by the inhibitor of janus kinases stimulates dormant human leukemia CD34(+)/CD38(-)cells and sensitizes them to, anti-leukemia agents. (2010)
  • Author(s): Ikezoe T
  • Journal Title: Int J Cancer Volume: 印刷中
  • Peer Reviewed
• [Presentation] CD82 regulates STAT5/IL-10 and supports survival of acute myelogenous leukemia Cell. (2012)
  • Author(s): Nishioka C
  • Organizer: 第54回米国血液学会
  • Place of Presentation: ジュージアワールドコンベンションセンター
  • Year and Date: 2012-12-09
• [Presentation] Blockade of mTOR sgnaling modulates expression of cytokines produced in HTLV-1-infected T cells. (2012)
  • Author(s): Nishioka C
  • Organizer: 第74回日本血液学会
  • Place of Presentation: 京都国際会館
  • Year and Date: 2012-10-20
• [Presentation] CD34+/CD38- leukemia stem cells aberrantly express CD82 adhesion molecule (2011)
  • Author(s): Nishioka C
  • Organizer: 第73回日本血液学会
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 2011-10-14
• [Presentation] Long-term exposure of leukemia cells to multitargeted tyrosine kinase inhibitor induces epigenetic silencing of PTEN gene (2010)
  • Author(s): Chie Nishioka
  • Organizer: 第72回日本血液学会・第52回日本臨床血液学会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2010-09-25
• [Presentation] Inhibition of MEK/ERK signaling induces apoptosis of AML cells viainhibition of 4E-BP1 and down-regulation of Mcl-1 (2010)
  • Author(s): Chie Nishioka
  • Organizer: 第69回日本癌学会学術総会
  • Place of Presentation: 大阪国際会議場
  • Year and Date: 2010-09-22
• [Presentation] CD34+/CD38-leukemia stem cells aberrantly express CD82 adhesion molecule. (2010)
  • Author(s): Takayuki Ikezoe
  • Organizer: 第52回米国血液学会総会
  • Place of Presentation: オーランド