難治性造血器腫瘍の分子病態と治療標的の解明

2007 Fiscal Year Annual Research Report

• Project/Area Number: 19679004
• Research Institution: The University of Tokyo
• Principal Investigator: 黒川 峰夫 The University of Tokyo, 医学部附属病院, 教授 (80312320)
• Keywords: 白血病 / 造血幹細胞 / Evi-1 / 白血病幹細胞

Research Abstract

本年度は、まず難治性白血病の原因遺伝子Evi-1の機能解明を行った。Evi-1を欠失する胎仔造血組織はin vitroで造血細胞を産生できないことが知られている。本研究において、われわれはEvi-1胎仔造血組織の造血能が、造血系転写因子GATA-2の導入やTGF-βシグナルの阻害により回復することを見いだした。Evi-1がGATA-2の発現を誘導することやTGF-βシグナルを阻害することがすでに知られているが、今回われわれが明らかにした知見はこれらの機能が造血発生にも重要であることを示唆する。一方、すでにわれわれは生後の造血細胞でEvi-1を欠失するマウスを作製した。本マウスでは未分化造血細胞の数が明らかに減少し、造血再構築能が著明に低下することから、Evi-1が造血幹細胞の維持に必須の遺伝子であることが判明している。本年度に行った解析により、われわれはEvi-1欠失造血細胞においてサイトカインによる増殖刺激への応答性が減弱していることを見いだし、Evi-1欠失による造血障害の一因を明らかとした。さらにわれわれはEvi-1の機能が個体の白血病においてどのような役割を担うかを解析した。Bcl2とc-Mycを導入したマウス骨髄細胞を放射線照射したマウスに移植すると、急激に白血病を発症して死亡する。ところが移植とともにBcl2/c-Myc導入骨髄細胞からEvi-1を欠失させると白血病の発症が明らかに遅延し、生存期間が有意に延長した。このことからEvi-1の個体造血における機能が、個体の白血病発症に重要な役割を果たすことが明らかとなった。

Research Products

• [Journal Article] AML1/Runx1 negatively regulates quiescent hematopoieticstem cells in adulthematopoiesis (2008)
  • Author(s): Ichikawa M, Goyama S, Asai T, Kawazu M, Nakagawa M, Takeshita M, Chiba S, Ogawa S, Kurokawa M.
  • Journal Title: The Journal of Immunology 180 Pages: 4402-4408
  • Peer Reviewed
• [Journal Article] AML1-Evi-1 specifically transforms hematopoietic stem cells throughfusion of the entire Evi-1 sequence to AML1 (2008)
  • Author(s): Takeshita M, Ichikawa M, Nitta E, Goyama S, Asai T, Ogawa S, Chiba S, Kurokawa M.
  • Journal Title: Leukemia 22 Pages: 1241-1249
  • Peer Reviewed
• [Journal Article] Drug-induced hypersensltivity syndrome with rapid hematopoietic reconstitution during treatment for acute myeloid leukemia (2008)
  • Author(s): Suzuki H, Asai T, Tamaki Z, Yoshimi A, Hangaishi A, Kanda Y, Motokura T, Chiba S, Kurokawa M.
  • Journal Title: Haematologica 93 Pages: 469-470
  • Peer Reviewed
• [Journal Article] Evi-1promotes para-aortic splanchnopleural hematopoiesis through up-regulation of GATA-2 and repression of TGF-βsignaling (2008)
  • Author(s): Sato T, Goyama S, Nitta E, Takeshita M, Yoshimi M, Nakagawa M, Nakagwa M, Kawazu M, Ichikawa M, Kurokawa M.
  • Journal Title: Cancer Science 99 Pages: 1407-1413
  • Peer Reviewed
• [Journal Article] Disseminated adenovirus disease by multiple adenovirus serotypes following alloogeneic hematopoietic stem cell transplantation (2008)
  • Author(s): Suzuki HI, Asai T, Okada K, Kazuyama Y, Takahashi T, Kanda Y, Chiba S, Kurokawa M.
  • Journal Title: Biology of Blood & Marrow Transplantation 14 Pages: 353-355
  • Peer Reviewed
• [Journal Article] The origin of neoplastic mast cells in systematic mastocytosis with AML1/ETO-positiveacute myeloid leukemia (2008)
  • Author(s): Nagai S, Ichikawa M, Takahashi T, Sato H, Yokota H, Oshima K, Izutsu K, Hangaishi A, Kanda Y, Motokura T, Chiba S, Yatomi Y, Kurokawa M.
  • Journal Title: Experimental Hematology 35 Pages: 1747-1752
  • Peer Reviewed
• [Journal Article] Decreased incidence of acute graft-versus-host disease by continuous infusion of cyclosporine with a higher target blood level (2008)
  • Author(s): Oshima K, Kanda Y, Nakasone H, Arai S, Nishimoto N, Sato H, Watanabe T, Hosoya N, Izutsu K, Asai T, Hangaishi A, Motokura T, Chiba S, Kurokawa M.
  • Journal Title: American Journal of Hematology 83 Pages: 226-232
  • Peer Reviewed
• [Journal Article] Late onset of autoimmune hemolytic anemia and pure red cell aplasia after allogeneic hematopoietic stem cell transplantation using in vivo alemtuzumab (2008)
  • Author(s): Kako S, Kanda Y, Oshlma K, Nlshimoto N, Sato H, Watanabe T, Hosoya N, Motokura T, Miyakoshi S, Taniguchi S, Kamijo A, Takahashi K, Chiba S, Kurokawa M.
  • Journal Title: American Journal of Hematology 83 Pages: 247-249
  • Peer Reviewed
• [Journal Article] False-positive Aspergillus galactomannan antigenaemia after haematopoietic stem cell transplantation (2008)
  • Author(s): Asano-Mori Y, Kanda Y, Oshima K, kako S, Shinohara A, Nakasone H, Kaneko M, Sato H, Watanabe T, Hosoya N, Izutsu K, Asai T, Hangaishi A, motokura T, Chiba S, Kurokawa M.
  • Journal Title: The Journal of Antimicrobial Chemotherapy 61 Pages: 411-416
  • Peer Reviewed
• [Journal Article] Both Notchl and Notch2 contribute to the regulation of melanocyte stem cells (2008)
  • Author(s): Kumano K, Masuda S, Sata M, Saito T, Lee SY, Yanagimoto-Sakata M, Tomita T, Iwatsubo T, Natsugari H, Kurokawa M, Ogawa S, Chiba S.
  • Journal Title: Pigment Cell Melanoma Research 21 Pages: 70-78
  • Peer Reviewed
• [Journal Article] Expression profiling of immature thymocytes revealed a novel homebox gene that regulates double-negative thymocyte development (2007)
  • Author(s): Kawazu M, Yamamoto G, Yoshimi M, Yamamoto K, Asai T, Ichikawa M, Seo S, Nakagawa M, Chiba S, Kurokawa M, Ogawa S.
  • Journal Title: The Journal of Immunology 179 Pages: 5445-5345
  • Peer Reviewed
• [Journal Article] Unbalanced translocation der(1;7)(q10;p10)deflnes a unique clinicopathological subgroup of myeloid neoplasms (2007)
  • Author(s): Sanada M, Uike N, Ohyashiki K, Ozawa K, Lili W, Hangaishi A, Kanda Y, Chiba S, Kurokawa M, Omine M, Mitani K, Ogawa S.
  • Journal Title: Leukemia 21 Pages: 992-997
  • Peer Reviewed
• [Journal Article] FDG-PET in T-cell and NK-cell neoplasms (2007)
  • Author(s): Kako S, Izutsu K, Ota Y, Minatani Y, Sugaya M, Momose T, Ohtomo K, Kanda Y, Chiba S, Motokura T, Kurokawa M.
  • Journal Title: Annals of Oncology 18 Pages: 1685-1690
  • Peer Reviewed
• [Journal Article] Early relapse of JAK2 V617F-positive chronic neutrophilic leukemia with central nervous system infiltration after unrelated bone marrow transplantation (2007)
  • Author(s): Kako S, Kanda Y, Sato T, Goyama S, Noda N, Shoda E, Osgima K, Inoue M, Izutsu K, Watanabe T, Motokura T, Chiba S, fukuyama M, Kurokawa M.
  • Journal Title: American Jounal of Hematology 82 Pages: 386-390
  • Peer Reviewed
• [Journal Article] Regression of the tumor after withdrawal of cyclospoorine in relapsed extranodal natural killer/T cell lymphoma following alloogeneic hematopoietic stem cell transplantation (2007)
  • Author(s): Kako S, Izutsu K, Oshima K, Sato H, Kanda Y, Motokura T, Chiba S, Kurokawa M.
  • Journal Title: American Journal of Hematology 82 Pages: 937-939
  • Peer Reviewed
• [Journal Article] A prospective study of cyclosporine A treatment of patients with low-risk myelodysplastic syndrome: presence of CD55(-)CD59(-)blood cells predicts platelet response (2007)
  • Author(s): Ishikawa T. Tohyama K, Nakao S, Yoshida Y, Teramura M, Motoji T, Takatoku M, Kurokawa M, Mitani K, Uchiyama T, Omine M.
  • Journal Title: International Journal of Hematology 86 Pages: 150-157
  • Peer Reviewed
• [Journal Article] Splenic peliosis in a patient with aplastic anemia during danazol therapy (2007)
  • Author(s): Arai S, Asai T, Uozaki H, Hangaishi A, Kanda Y, Motokura T, Chiba S, Kurokawa M.
  • Journal Title: International Journal of Hematology 86 Pages: 329-332
  • Peer Reviewed
• [Journal Article] Presumptive treatment strategy for aspergillosis in allogeneic haematopoietic stem cell transplant recipients (2007)
  • Author(s): Oshima K, Kanda Y, Asano-Mori Y, Nishimoto N, Arai S, Nagai S, Sato H, Watanabe T, Hosoya N, Izutsu K, Asai T, Hangaishi A, Motokura T, Chiba S, Kurokawa M.
  • Journal Title: The Journal of Antimicrobial Chemotherapy 60 Pages: 350-355
  • Peer Reviewed
• [Journal Article] Long-term sustained mixed chimerism after allogeneic stem cell transplantation in a patient with severe aplastic anemia (2007)
  • Author(s): Saito AM, Chiba S, Ogawa S, Kanda Y, Hirai H, Kurokawa M.
  • Journal Title: Internal Medicine 46 Pages: 1923-1926
  • Peer Reviewed
• [Journal Article] Highly sensitive method for genome-wide detection of allelic composition in nonpaired, primary tumor specimens by use of affymetrix single-nucleotide-polyraorphism genotyping microarrays (2007)
  • Author(s): Yamamoto G, Nannya Y, Kato M, Sanada M, Levine RL, Kawamata N, Hangaishi A, Kurokawa M, Chiba S, Gilliland DG, Koeffler HP, Ogawa S.
  • Journal Title: American Journal of Human Genetics 81 Pages: 114-126
  • Peer Reviewed
• [Journal Article] Evaluation of genome-wide power of genetic association studies based on empirical data from the hapmap project (2007)
  • Author(s): Nannya Y, Taura K, Kurokawa M, Chiba S, Ogawa S.
  • Journal Title: Human Molecular Genetics 16 Pages: 2494-2505
  • Peer Reviewed
• [Journal Article] Immunotherapy against metastatic renal cell carcinoma with mature dendritic cells (2007)
  • Author(s): Matsumoto A, Haraguchi K, Takahashi T, Azuma T, Kanda Y, Tomita K, Kurokawa M, Ogawa S, Takahashi K, Chiba S, Kitamura T.
  • Journal Title: International Journal of Urology 14 Pages: 277-283
  • Peer Reviewed
• [Presentation] 造血系転写因子と白血病(教育講演) (2007)
  • Author(s): 黒川峰夫
  • Organizer: 第69回日本血液学会・第49回日本臨床血液学会
  • Place of Presentation: 横浜市
  • Year and Date: 2007-10-13
• [Presentation] 転写因子による造血制御と白血病発症機構(シンポジウム) (2007)
  • Author(s): 黒川峰夫
  • Organizer: 第66回日本癌学会学術総会
  • Place of Presentation: 横浜市
  • Year and Date: 2007-10-04
• [Presentation] Transcription factors in hematopolesis and leukemogenesis (2007)
  • Author(s): 黒川峰夫
  • Organizer: The 4th AML/MDS Working Party Symposium Korea-Japan Joint Symposium
  • Place of Presentation: 韓国・釜山市
  • Year and Date: 2007-09-07