AML1の機能不全による造血異常と白血病発症機構の解明

• Project/Area Number: 18013014
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• 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)
• Co-Investigator(Kenkyū-buntansha): 河津 正人 東京大学, 医学部・附属病院, 医員 (20401078)
• Project Period (FY): 2006 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥12,400,000 (Direct Cost: ¥12,400,000); Fiscal Year 2007: ¥6,300,000 (Direct Cost: ¥6,300,000); Fiscal Year 2006: ¥6,100,000 (Direct Cost: ¥6,100,000)
• Keywords: 白血病発症 / がん幹細胞 / 転写因子 / 染色体転座 / 白血病 / 転写遺伝子 / AML1

Research Abstract

昨年度われわれはAML1機能不全が造血幹細胞活性を亢進させることを明らかにした。本年度は、まずAML1欠失による白血病幹細胞活性の亢進を検証した。白血病遺伝子MIL-ENLを骨髄細胞に導入しマウスに移植することにより白血病発症を再現できる。この系でAML1を欠失した骨髄細胞を用いると、対照と比較して早期に白血病を発症した。すなわち、AML1欠失は白血病発症を加速する。そこで白血病においてAML1機能不全が白血病幹細胞の生成と維持をもたらすことを、Evi-1の活性化を付加的遺伝子異常として用いることにより検証した。AML1欠失骨髄造血前駆細胞にEvi-1を導入し、コロニー形成アッセイにて細胞の不死化を評価した。AML1欠失骨髄細胞は正常対照と比較してコロニー形成能の延長を認めるが、これにEvi-1を強制発現させても細胞の不死化には至らなかった。AML1-Evi-1のEvi-1部分の欠失変異体も細胞の不死化を誘導できず、AML1-Evi-1による白血病発症にはAML1の機能欠失とEvi-1機能の亢進のみならず、AML1とEvi-1全長の融合が必須であることが示された。さらに、AML1の機能欠失によって白血病幹細胞化する造血幹細胞分画を同定するため、マウス骨髄細胞から造血幹細胞(HSC)・骨髄球系共通前駆細胞・顆粒球・マクロファージ前駆細胞を精製し、それらにAML1の機能抑制型変異遺伝子であるAML1-Evi-1およびAML1-ETOを導入し、細胞の形質転換を比較した。結果、AML1-ETOはこれらの3分画を全て形質転換できるが、AML1-Evi-1はHSC分画のみを形質転換することが示された。以上の結果から、AML1機能不全は白血病幹細胞活性の亢進をもたらすが、白血病幹細胞の発生およびその標的細胞分画はAML1と融合した変異遺伝子に依存していることが明らかとなった。

Research Products

• [Journal Article] AML1/Runx1 negatively regulates quiescent hematopoietic stem cells in adult hematopoiesis. (2008)
  • Author(s): Ichikawa M, Goyama S, Asai T, Kawazu M, Nakagawa M, Takeshita M, Chiba S, Ogawa S, and 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, GoyamaS, Asai T, Ogawa S, and Kurokawa M.
  • Journal Title: Leukemia
• [Journal Article] Evi-1 promotes para-aortic splanchnopleural hematopoiesis through up-regulation of GATA-2 and repression of TGF-β signaling. (2008)
  • Author(s): Sato T, Goyama S, Nitta E, Takeshita M, Yoshimi M, Nakagawa M, Nakagwa M, Kawazu M, Ichikawa M, and Kurokawa M.
  • Journal Title: Cancer Science
  • NAID: 10024008671
• [Journal Article] The origin of neoplastic mast cells in systematic mastocytosis with AML1/ETO-positive acute myeloid luekemia. (2008)
  • Author(s): Nagai S, Ichikawa M, Takahashi T, Sato H, Yokota H, Oshima K, Izutsu K, HangaishiA, Kanda Y, Motokura T, Chiba S, Yatomi Y, Kurokawa M.
  • Journal Title: Experimental Hematology 35 Pages: 1747-1752
  • 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: Journal of Antimicrobial Chemotherapy 61 Pages: 411-416
  • Peer Reviewed
• [Journal Article] Disseminated adenovirus disease by multiple adenovirus serotypes following allogeneic 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] FDG-PET in T-cell and NK-cell neoplasms. (2007)
  • Author(s): Kako S, Izutsu K, Ota Y, Minatani Y, SugayaM, Momose T, Ohtomo K, Kanda Y, ChibaS, Motokura T, Kurokawa M.
  • Journal Title: Annals of Oncology 18 Pages: 1685-1690
  • 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
  • NAID: 130000078607
  • 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] 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: Journal of Antimicrobial Chemotherapy 60 Pages: 350-355
  • 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] Highly sensitive method for genomewide detection of allelic composition in nonpaired, primary tumor specimens by use of affymetrix single-nucleotide-polymorphism 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] Unbalanced translocation der(1;7)(q10;p10)defines 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] 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, NodaN, 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] 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] Splenic Peliosis in a patient with aplastic anemia during danzaol 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] 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, Takatouku M, Kurokawa M, Mitani K, Uchiyama T, Omine M.
  • Journal Title: International Journal of Hematology 86 Pages: 150-157
  • NAID: 10019733994
  • Peer Reviewed
• [Journal Article] Durable remission after the administration of rituximab for EBV negative diffuse large B-cell lymphoma arising after autologous peripheral blood stem cell transplantation for angioimmunoblastic T-cell lymphoma. (2007)
  • Author(s): Shinohara A, Asai T, Izutsu K, Ota Y, Takeuchi K, Hangaishi A, Kanda Y, Chiba S, Motokura T, Kurokawa M.
  • Journal Title: Leukemia and Lymphoma 48 Pages: 418-420
• [Journal Article] A high incidence of late-onset neutropenia following rituximab-containing chemotherapy as a primary treatment for CD20-positive B-cell lymphoma : a single institution study. (2007)
  • Author(s): Nitta E, Izutsu K, Sato T, Ohta Y, Takeuchi K, Kamijo A, Oshima K, Kanda Y, Chiba S, Motokura T, Kurokawa M
  • Journal Title: Annals of Oncology 18 Pages: 364-349
• [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, Oshima K, Inoue M, Izutsu K, Watanabe T, Motokura T, Chiba S, Fukayama M, Kurokawa M
  • Journal Title: American Journal of Hematology 82 Pages: 386-390
• [Journal Article] AML1/Runx1 as a versatile regulator of hematopoiesis : regulation of its function and a role in adult hematopoiesis (2006)
  • Author(s): Kurokawa M.
  • Journal Title: Journal of Hematology 84 Pages: 136-142
  • NAID: 10019284779
• [Journal Article] AML1/Runx1 rescues Notchl-Null mutation-induced deficiency of para-aortic splanchnopleural hematopoiesis of para-aortic splanchnopleural hematopoiesis. (2006)
  • Author(s): Nakagawa M, Ichikawa M, Kumano K, Coyama S, Kawazu M, Asai T, Ogawa S, Kurokawa M, Chiba S.
  • Journal Title: Blood 15 Pages: 3329-3334
• [Journal Article] Regression of the tumor after withdrawal of cyclosporine in relapsed extranodal natural killer/T cell lymphoma following allogeneic hematopoietic stem cell transplantation.
  • Author(s): Kako S, Izutsu K, Arai T, Yokoyama Y, Oshima K, Sato H, Asai T, Watanabe T, Hangaishi A, Kanda Y, Motokura T, Chiba S, Kurokawa M
  • Journal Title: American Journal of Hematology (in press)
• [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 (2007)
  • Author(s): 黒川 峰夫
  • Organizer: 第66回日本癌学会学術総会 (シンポジウム)
  • Place of Presentation: 横浜市
  • Year and Date: 2007-10-04
• [Presentation] Transcription factors in hematopoiesis 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