慢性骨髄性白血病急性転化のメカニズムの解明および早期遺伝子診断の確立

• Project/Area Number: 13218096
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Kyushu University
• Principal Investigator: 下田 和哉 九州大学, 大学病院, 助手 (90311844)
• Project Period (FY): 2001 – 2004
• Project Status: Completed (Fiscal Year 2004)
• Budget Amount: ¥37,900,000 (Direct Cost: ¥37,900,000); Fiscal Year 2004: ¥12,100,000 (Direct Cost: ¥12,100,000); Fiscal Year 2003: ¥9,100,000 (Direct Cost: ¥9,100,000); Fiscal Year 2002: ¥9,000,000 (Direct Cost: ¥9,000,000); Fiscal Year 2001: ¥7,700,000 (Direct Cost: ¥7,700,000)
• Keywords: G-CSF / Stat3 / C / EBPα / Tyk2 / IFN-α / Rack-1 / 慢性骨髄性白血病 / 急性転化 / インターフェロン α / Jakキナーゼ / Stat / CML / blstic crisis / SHIP-1 / マイクロアレイ

Research Abstract

白血病は正常の好中球造血メカニズムの破綻が原因と考えられる。好中球分化に必須なサイトカインである顆粒球コロニー刺激因子(G-CSF)刺激時に主に活性化されるStat3の下流に位置するシグナル伝達物質の同定を行い、G-CSF刺激時に活性化されるStat3は、C/EBPαの発現を上昇させることにより好中球分化を促進していることを見出した。しかし、血球特異的Stat3欠損マウスでは、好中球系細胞は存在し、減少ではなくむしろ増加していた。またG-CSF刺激によるコロニー形成能や細胞増殖能は、Stat3が欠損するとより亢進しており、Erkの恒常的活性化が見られた。よってin vivoでは、G-CSF刺激で活性化されるStat3はG-CSFのシグナルを負に制御すること、G-CSFによる好中球造血はMAPキナーゼを介する経路により行われることを明らかにした。
さらに、CMLの治療に用いられ、骨髄細胞増殖抑制作用があるIFN-αの作用機序の解析を行った。JakキナーゼであるTyk2の欠損マウスを作成し、IFN-αのシグナル伝達におけるTyk2の役割を検討した。IFN-αによる造血細胞増殖抑制作用は、Tyk2欠損時には消失し、IFN-αによる造血抑制のシグナル伝達にはTyk2が必須であった。また、IFN-αによるB細胞増殖の抑制は、Tyk2の下流の転写因子であるStat1欠損細胞ではみとめられず、JakキナーゼであるTyk2が、Stat以外のシグナル伝達物質を介してIFN-αの細胞増殖抑制シグナルを伝達することを明らかにし、その候補として、Rack-1(Receptor for activated C kinase1)をクローニングした。

Research Products

• [Journal Article] The roles of Stat3 and ERK in G-CSF signaling. (2005)
  • Author(s): Kamezaki K et al.
  • Journal Title: Stem Cells 23 Pages: 252-263
• [Journal Article] Physical and functional interactions between Daxx and DNA methyltransferase 1 associated protein, DMAP. (2004)
  • Author(s): Muromoto R et al.
  • Journal Title: J Immunol 172 Pages: 2985-2993
• [Journal Article] Tyk2 is essential for IFN-a-induced gene expression in mast cells. (2004)
  • Author(s): Mori Y et al.
  • Journal Title: International Archives of Allergy and Immunology 134 Pages: 25-29
• [Journal Article] Physical and Functional Interactions between Daxx and TSG101. (2004)
  • Author(s): Muromoto R et al.
  • Journal Title: Biochem.Biophys.Res.Commun. 316 Pages: 827-833
• [Journal Article] Tyk2 interacts with and phosphorylates Rack-1,a WD motif containing protein. (2004)
  • Author(s): Haro T et al.
  • Journal Title: J Immunol 173 Pages: 1151-1157
• [Journal Article] Hapten-Induced Contact Hypersensitivity is enhanced in Tyk2-Deficient Mice. (2004)
  • Author(s): Hosogia M et al.
  • Journal Title: J Dermatol Sci 36 Pages: 51-56
• [Journal Article] Human Cord Blood- and Bone Marrow-derived CD34^+ Cells Regenerate Gastrointestinal Epithelial Cells. (2004)
  • Author(s): Ishikawa F et al.
  • Journal Title: FASEB Journal 18 Pages: 1958-1960
• [Journal Article] The role of Tyk2, Stat1 and Stat4 in LPS-induced endotoxin signals. (2004)
  • Author(s): Kamezaki K et al.
  • Journal Title: Int Immunol 16 Pages: 1173-1179
• [Journal Article] Signal transducers and activators of transcription 3 augments the transcriptional activity of CCAAT/enhancer binding protein a in G-CSF signaling pathway.
  • Author(s): Numata A et al.
  • Journal Title: Journal of Biological Chemistry (印刷中)
• [Journal Article] Physical and functional interactions between STAP-2/BKS and STAT5.
  • Author(s): Sekine Y et al.
  • Journal Title: Journal of Biological Chemistry (印刷中)
• [Journal Article] Transgenic Mice Overexpressing Murine Thrormbopoietin Develop Myelofibrosis and Osteosclerosis.
  • Author(s): Kakumitsu H et al.
  • Journal Title: Leukemia Research (印刷中)
• [Publications] Aoki K, Shimoda K et al.: "Limitin, an interferon-like cytokine, transduces inhibitory signals on B-cell growth through activation of Tyk2, but not Stat1, followed by the induction and nuclear translocation of Daxx."Experimaental Hematology. 31. 1317-1322 (2003)
• [Publications] Kato K, Kamezaki K, Shimoda K et al.: "Intracellular signal transduction of interferon on the suppression of haematopoietic progenitor cell growth."British Journal of Haematology. 123. 528-535 (2003)
• [Publications] Kamezaki K, Shimoda K et al.: "The lipocalin 24p3, which is an essential molecule in IL-3 withdrawal-induced apoptosis, is not required in the G-CSF withdrawal-induced apoptosis."European Journal of Haematology. 71. 412-417 (2003)
• [Publications] Seto Y, Nakajima H, Suto A, Shimoda K, et al.: "Enhanced Th2 Cell-mediated Allergic Inflammation in Tyk2-deficient Mice."Journal of Immunology. 170. 1077-1083 (2003)
• [Publications] Muromoto R, Shimoda K et al.: "Physical and functional interactions between Daxx and DNA methyltransferasel associated protein, DMAP."Journal of Immunology. 印刷中. (2004)
• [Publications] Shimoda K et al.: "Tyk is required for the induction and nuclear translocation of Daxx which regulates IFNα induced suppression of B lymphocyte formation"Journal of Immunology. 169. 4707-4711 (2002)
• [Publications] Shimoda K et al.: "Partial impairment of interleukin-12(IL-12) and IL-18 signaling in tyk2-deficient mice"Blood. 99. 2094-2099 (2002)
• [Publications] Seto Y et al.: "Enhanced Th2 Cell-mediated Allergic Inflammation in Tyk2-deficient Mice"Journal of Immunology. 170. 1077-1083 (2003)
• [Publications] Shimoda K et al.: "Partial impairment of IL-12 and IL-18 signaling in Tyk2-deficient mice"Blood. (in press).
• [Publications] Yakushiji K et al.: "Monitoring of cytomegalovirus reaction after allogenic stem cell transplantation : comparison of an antigenemia assay and quantitative real-time polymerase chain reaction"Bone Marrow Transplantation. (in press).
• [Publications] Numata A et al.: "Therapy-related chronic myelogenous leukemia following autologous stem cell transplantation for Ewing's sarcoma"British J Haematol. (in press).
• [Publications] Asano Y et al.: "Immunosuppressive therapy for patients with refractory anemia"Annual of Hematology. 80. 634-638 (2001)
• [Publications] Sugio Y et al.: "Ticlopidine-associated thrombotic thrombocytopenic purpura with an IgG-type inhibitor to von Willebrand factor-cleaving protease activity"International Journal of Hematology. 74. 347-351 (2001)