難治性造血器腫瘍の分子病態と治療標的の解明

2008 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 / 白血病幹細胞 / Evi-1 / AML1

Research Abstract

本年は、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。DNAのメチル化やヒストン修飾などのエビジェネティクスが造血器腫癌の発症・進展に重要であることが知られているが、われわれはEvi-1が複数のヒストンメチル化酵素(HMT)と結合することを見出した。また、Evi-1-HMT複合体がHMT活性を有することを確認した。さらに、PAI-1プロモーターを用いたレポーター解析を行い、Evi-1によるTGF-βシグナル阻害にこれらのHMTが重要であることを明らかにした。Evi-1は転写制御因子P/CAF,CtBP,HDACやクロマチンリモデリング因子BRGlなどと結合し、複合体を形成して転写制御を行うと考えられている。今回の結果から、Evi-1による転写制御にヒストンメチル化修飾も重要な役割を果たすことが明らかとなった。
これと並行して、白血病において変異がみられる転写因子AML1の機能欠失が白血病発症に果たす役割を解析した。マウス骨髄細胞に白血病遺伝子MLL-ENLを導入しマウスに移植すると白血病が発症するが、AML1を欠失する骨髄細胞にMLL-ENLを導入すると、白血病が対照より早期に発症した。さらに、純化した造血幹細胞にAML1欠失を誘導しcDNAマイクロアレイを用いたトランスクリプトーム解析を行うことにより、造血幹細胞におけるAMLlの転写標的ネットワークの同定を試みた。データベース解析との組み合わせにより、AMLl欠失によるNF-κBシグナルの活性化が明らかとなった。すなわち、AML1の欠失はNF-κB経路を介して白血病幹細胞活性に関与する可能性が示唆された。
これらの成果は、Evi-1やAML1がエビジェネティツクな制御や細胞内シグナルの制御を介して白血病幹細胞活性に関与することを示すものであり、治療標的の同定による白血病の克服においても重要な知見である。

Research Products

• [Journal Article] Evidence for basophilic differentiation of acute promyelocytic leukemia cells during arsenic trioxide therapy. (2009)
  • Author(s): Masamoto Y, Nannya Y, Arai S, Koike Y, Hangaishi A, Yatomi Y, and Kurokawa M.
  • Journal Title: British Journal of Haematology 144 Pages: 798-799
  • Peer Reviewed
• [Journal Article] Influence of pretransplantation serum ferritin on nonrelapse mortality after myeloablative and nonmyeloablative allogeneic hematopoietic stem cell transplantation. (2009)
  • Author(s): Kataoka K, Nannya Y, Hangaishi A, Imai Y, Chiba S, Takahashi T, and Kurokawa M.
  • Journal Title: Biology of Blood and Marrow Transplantation 15 Pages: 195-204
  • Peer Reviewed
• [Journal Article] Successful haematopoietic stem cell transplantation from an HLA-identical sibling in a patient with aplastic anemia following HLA-haploidentical living-related liver transplantation for fulminant hepatitis. (2009)
  • Author(s): Yoshimi A, Nannya Y, Asano D, Yamamoto G, Kumano K, Hangaishi A, Matsui Y, Takahashi T, Imai Y, Kokudo N, and Kurokawa M.
  • Journal Title: Biology of Blood and Marrow Transplantation 15 Pages: 389-390
  • Peer Reviewed
• [Journal Article] Acute eosinophilic pneumonia is a non-infectious lung complication after allogeneic hematopoietic stem cell transplantation. (2009)
  • Author(s): Yoshimi M, Nannya Y, Watanabe T, Asai T, Ichikawa M, Yamamoto G, Kumano K, Hangaishi A, Imai Y, Takahashi T, Chiba S, and Kurokawa M.
  • Journal Title: International Journal of Hematology 89 Pages: 244-248
  • Peer Reviewed
• [Journal Article] A new three-way variantt(15;22;17)(q22;q11.2;q21) in acute promyelocytic leukemia. (2009)
  • Author(s): Kato T, Hangaishi A, Ichikawa M, Motokura T, Takahashi T, and Kurokawa M.
  • Journal Title: International Journal of Hematology 89 Pages: 204-208
  • Peer Reviewed
• [Journal Article] Pathogenetic significance of EVI-1 in hematological malignancies. (2009)
  • Author(s): Goyama S and Kurokawa M.
  • Journal Title: Cancer Science (in press)
  • Peer Reviewed
• [Journal Article] The race and dose of chemotherapy should be considered for optimizing maintenance therapy for acute promyelocytic leukemia. (2009)
  • Author(s): Nagai S, Nannya Y, Hangaishi A, Takahashi T, and Kurokawa M.
  • Journal Title: Leukemia Research (in press)
  • Peer Reviewed
• [Journal Article] Simultaneous appearance of methotrexate-associated lymphoproliferative disorder and tuberculous meningitis demonstrating the definitive role of immunosuppression. (2009)
  • Author(s): Nagai 5, Izutsu K, Watanabe T, and Kurokawa M.
  • Journal Title: Annals of Hematology (in press)
  • Peer Reviewed
• [Journal Article] Hemoperitoneum due to spontaneous rupture of the left gastroepiploic artery in a patient with hemophilia A. (2009)
  • Author(s): Yoshimi A, Takahashi T, Motokura T, Yatomi Y, Chiba S, and Kurokawa M.
  • Journal Title: Annals of Hematology (in press)
  • Peer Reviewed
• [Journal Article] Early onset of acute lymphoblastic leukemia with MLL rearrangement after autologous stem cell transplantation for multiple myeloma. (2009)
  • Author(s): Ueda K, Yamamoto G, Shinohara A, Hangaishi A, and Kurokawa M.
  • Journal Title: Annals of Hematology (in press)
  • Peer Reviewed
• [Journal Article] Monitoring trough concentration of voriconazole is important to ensure successful antifungal therapy and to avoid hepatic damage in patients with hematological disorders. (2009)
  • Author(s): Ueda K, Nannya Y, Kumano K, Hangaishi A, Takahashi T, Imai Y, and Kurokawa M.
  • Journal Title: International Journal of Hematology (in press)
  • Peer Reviewed
• [Journal Article] Chronic myelomonocytic leukemia presenting as hemorrhagic shock due to uterine infiltration of leukemic cells and early-stage endometrial adenocarcinoma. (2009)
  • Author(s): Yoshimi A, Asai T, Maeda D, Hangaishi A, Sakatani T, Takahashi T, Imai Y, Fukayama M, and Kurokawa M.
  • Journal Title: Archives of Gynecology and Obstetrics (in press)
  • Peer Reviewed
• [Journal Article] Evi-1 is a critical regulator for hematopoietic stem cells and transformed leukemic cells. (2008)
  • Author(s): T, Ichikawa M, Ogawa S, Chiba S, and Kurokawa M.
  • Journal Title: Cell Stem Cell 3 Pages: 207-220
  • Peer Reviewed
• [Journal Article] Successful engraftment following HLA-mismatched cord blood transplantation for patients with anti-HLA antibodies. (2008)
  • Author(s): Kataoka K, Yamamoto G, Nannya Y, Yoshimi A, Okada S, Asai T, Kumano K, Hangaishi A, Takahashi T, Chiba S, and Kurokawa M.
  • Journal Title: Bone Marrow Transplantation 42 Pages: 129-130
  • Peer Reviewed
• [Journal Article] Antileukemic immunity associated with antineutrophil antibody production after allogeneic hematopoietic stem cell transplantation for myeloid/NK-cell precursor acute leukemia. (2008)
  • Author(s): Suzuki H, Suzuki T, Kamijo A, Ohta S, Sato H, Hangaishi A, Takahashi T, Kanda Y, Motokura T, Chiba S, and Kurokawa M.
  • Journal Title: Antileukemic immunity associated with antineutrophil antibody production after allogeneic hematopoietic stem cell transplantation for myeloid/NK-cell precursor acute leukemia. 42 Pages: 285-287
  • Peer Reviewed
• [Journal Article] Ovarian shielding allows ovarian recovery and normal birth in female hematopoietic SCT recipients undergoing TBI. (2008)
  • Author(s): Nakagawa K, Kanda Y, Yamashita H, Nakagawa S, Sasano N, Ohtomo K, Oshima K, Kumano K, Ban N, Minamitani Y, Kurokawa M, and Chiba S.
  • Journal Title: Bone Marrow Transplantation 42 Pages: 697-699
  • Peer Reviewed
• [Journal Article] Simultaneous appearance of central nervous system relapse and subarachnoid hemorrhage during or after targeted therapies for acute promyelocytic leukemia (2008)
  • Author(s): Nagai S, Asai T, Watanabe T, Oshima K, Hangaishi A, Kanda Y, Motokura T, Chiba S, Aoki S, Ohtomo K, and Kurokawa M.
  • Journal Title: Annals of Hematology 87 Pages: 593-595
  • Peer Reviewed
• [Journal Article] Hemorrhagic cystitis in a patient receiving gemtuzumab ozogamicin for relapsed acute promvelocytic leukemia after cord blood transplantation. (2008)
  • Author(s): Yoshimi A, Asai T, Hangaishi A, Takahashi T, Chiba S, and Kurokawa M.
  • Journal Title: Annals of Hematology 87 Pages: 851-852
  • Peer Reviewed
• [Journal Article] Long-term ultra-low-dose acyclovir against varicella-zoster virus reactivation after allogeneic hematopoietic stem cell transplantation. (2008)
  • Author(s): Asano-Mori Y, Kanda Y, OshimaK, Kako S, Shinohara A, Nakasone H, Sato H, Watanabe T, Hosoya N, IzutsuK, Asai T, Hangaishi A, Motokura T, Chiba S, and Kurokawa M.
  • Journal Title: American Journal of Hematology 83 Pages: 472-476
  • Peer Reviewed
• [Journal Article] Conventional allogeneic hematopoietic stem cell transplantation for lymphoma may overcome poor prognosis associated with positive FDG-PET scan before transplantation. (2008)
  • Author(s): Yoshimi A, Izutsu K, Takahashi M, Oshima K, Kako S, Kanda Y, Motokura T, Chiba S, Momose T, Ohtomo K, and Kurokawa M.
  • Journal Title: American Journal of Hematology 83 Pages: 477-481
  • Peer Reviewed
• [Journal Article] A myeloablative conditioning regimen for patients with impaired cardiac function undergoing allogeneic stem cell transplantation: reduced cyclophosphamide combined with etoposide and total body irradiation. (2008)
  • Author(s): Yoshimi A, Nannya Y, Sakata-Yanagimoto M, Oshima K, Takahashi T, Kanda Y, Motokura T, Chiba S, and Kurokawa M.
  • Journal Title: American Journal of Hematology 83 Pages: 635-639
  • Peer Reviewed
• [Journal Article] Multicenter prospective trial evaluating the tolerability of imatinib for Japanese patients with chronic myelogenous leukemia in the chronic phase: Does body weight matter? (2008)
  • Author(s): Kanda Y, Okamoto S, Tauchi T, Kisaki M, Inokuchi K, Yabe M, Yokoyama K, Ito Y, Kimura Y, Higasbibara M, Bessho M, Ando K, Chiba S, Kurokawa M, Oshimi K, Dan K, Ohyashiki K, and Ikeda Y.
  • Journal Title: American Journal of Hematology 83 Pages: 835-839
  • Peer Reviewed
• [Journal Article] A case of adult Langerhans cell histiocytosis showing successfully regenerated osseous tissue of the skull after chemotherapy. (2008)
  • Author(s): Suzuki T, Izutsu K, Kako S, Ohta S, Hangaishi A, Kanda Y, Motokura T, Chiba S, and Kurokawa M.
  • Journal Title: Internatinal Journal of Hematology 87 Pages: 284-288
  • Peer Reviewed
• [Journal Article] Clinical features of late cytomegalovirus infection after hematopoietic stem cell transplantation. (2008)
  • Author(s): Asano-Mori Y, Kanda Y, Oshima K, Kako S, Shinohara A, Nakasone H, Sato H, Watanabe T, Hosoya N, Izutsu K, Asai T, Hangaishi A, Motokura T, Chiba S, and Kurokawa M.
  • Journal Title: International Journal of Hematology 87 Pages: 310-318
  • Peer Reviewed
• [Journal Article] Elevated serum levels in interleukin-2 receptor in chronic eosinophilic leukemia / hypereosinophilic syndrome with FIP1L1-PDGFRα fusion gene. (2008)
  • Author(s): Kataoka K, Izutsu K, Nagai S, Hangaishi A, Motokura T, Takahashi T, and Kurokawa M.
  • Journal Title: International Journal of Hematology 87 Pages: 440-441
  • Peer Reviewed
• [Journal Article] ESHAP therapy was very effective for a patient with Langerhans cell sarcoma. (2008)
  • Author(s): Yoshimi A, Kumano K, Motokura T, Takazawa Y, Oota S, Chiba S, Takahashi T, Fukayama M, and Kurokawa M.
  • Journal Title: International Journal of Hematology 87 Pages: 532-537
  • Peer Reviewed
• [Journal Article] Herpes simplex encephalitis and subsequent cytomegalovirus encephalitis after chemoradiotherapy for central nervous system relapse of diffuse large B-cell lymphoma: a case report and literature review. (2008)
  • Author(s): Suzuki H, Hangaishi A, Hosoya N, Watanabe T, Kanda Y, Motokura T, Chiba S, and Kurokawa M.
  • Journal Title: International Journal of Hematology 87 Pages: 538-541
  • Peer Reviewed
• [Journal Article] Late onset pneumatosis cystoides intestinalis associated with non-infectious pulmonary complinations after allogeneic hematopoietic stem cell transplantation. (2008)
  • Author(s): Suzuki H, Izutsu K, Nagai S, Watanabe T, Oshima K, Kanda Y, Motokura T, Chiba S, and Kurokawa M.
  • Journal Title: International Journal of Hematology 88 Pages: 116-118
  • Peer Reviewed
• [Journal Article] Molecular and cytogenetic response of chronic myelogenous leukemia treated with imatinib mesvlate: one institutional experience in Japan. (2008)
  • Author(s): Nannya Y, Yokota H, Sato Y, Yamamoto G, Asai T, Ichikawa M, Watanabe T, Kumano K, Hangaishi A, Takahashi T, Chiba S, and Kurokawa M.
  • Journal Title: International Journal of Hematology 88 Pages: 159-164
  • Peer Reviewed
• [Journal Article] Expression and tyrosine phosphorylation of Crk associated substrate lymphocyte type (Cas-L) protein in human neutrophils. (2008)
  • Author(s): Nakamoto T, Seo S, Sakai R, Kato T, Kutsuna H, Kurokawa M, Nods M, Miyasaka N, and Kitagawa S.
  • Journal Title: Journal of Cellular Biochemistry 105 Pages: 121-128
  • Peer Reviewed
• [Journal Article] Case Report: Persistent cytomegalovirus (CMV) infection after haploidentical hematopoietic stem cell transplantation using in vivo alemtuzumab: emergence of resistant CMV due to mutations in the UL97 and UL54 genes. (2008)
  • Author(s): Oshima K, Kanda Y, Kako S, Asano-Mori Y, Watanabe T, Motokura T, Chiba S, Shiraki K, and Kurokawa M.
  • Journal Title: Journal of Medical Virology 80 Pages: 1769-1775
  • Peer Reviewed
• [Presentation] 造血系転写因子と白血病 (2008)
  • Author(s): 黒川峰夫
  • Organizer: 第70回日本血液学会総会
  • Place of Presentation: 京都市
  • Year and Date: 2008-10-10
• [Presentation] The pathogenetic significance of deregulated transcription factors in hematological malignancies (2008)
  • Author(s): Kurokawa, M.
  • Organizer: The Uehara Memorial Foundation Symposium
  • Place of Presentation: 東京都
  • Year and Date: 2008-07-01