難治性造血器腫瘍の分子病態と治療標的の解明

2009 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

Research Abstract

MLLはMLL-ENL,MLL-AF9などの融合遺伝子を形成して難治性白血病を引き起こす。これまでにわれわれはEvi-1欠失マウスを用いて、MLL融合遺伝子の白血病原性にEvi-1が重要な役割を果たすことを見いだしている。さらに今回、MLL-ENLが造血幹細胞特異的にEvi-1のプロモーターを活性化してその発現を上昇させることを明らかとした(投稿中)。MLL白血病ではしばしばEvi-1が高発現することが知られていたが、本知見はその分子基盤を明らかにしたものとして注目される。さらにわれわれは、ヒトでEvi-1を高発現するMLL-ENL白血病が造血幹細胞に近い遺伝子発現パターンを示すことを見いだした。MLL白血病の中でもEvi-1高発現症例はより予後不良であることが知られているが、今回の知見から、Evi-1が白血病幹細胞の生成・維持を通してMLL白血病の難治性に関与することが推測される。
われわれはこれまでに条件的Evi-1欠失マウスを樹立・解析し、Evi-1が造血幹細胞の維持に必須の遺伝子であることを示している。今回われわれはマイクロアレイを用いて、ノックアウトマウスの造血細胞でEvi-1欠失により発現の変化する遺伝子をゲノムワイドに探索した。その結果、Evi-1により発現が誘導される遺伝子としてPbx1を同定した(Shimabe M, et al.Oncogene 28 : 4364-74, 2009)。Pbx1は造血幹細胞に発現する遺伝子であり、本研究はEvi-1によるPbx1制御が、造血幹細胞で重要な役割を果たす可能性を提起したものとして注目される。一方、造血細胞のコロニー形成アッセイを用いて、Evi-1による造血細胞の形質転換能を解析することができる。Pbx1をsiRNAによりノックダウンすると、Evi-1によるコロニー形成能は著明に減少し、Pbx1がEvi-1の白血病原性にも重要な役割を果たすことが明らかとなった。

Research Products

• [Journal Article] AML1 enhances the epression of leukotriene B4 type-1 receptor in leukocytes. (2010)
  • Author(s): Hashidate T, Nakamura M, Nakagawa M, Ichikawa M, Kurokawa M, Shimizu T.
  • Journal Title: FASEB Journal (in press)
  • Peer Reviewed
• [Journal Article] Essential roles of VLA-4 in the hematopoietic system. (2010)
  • Author(s): Imai Y, Shimaoka M, Kurokawa M.
  • Journal Title: International Journal of Hematology (in press)
  • Peer Reviewed
• [Journal Article] The impact of molecularly targeted therapies upon the understanding of leukemogenesis and the role of hematopietic stem cell transplantation in acute promyelocytic leukemia. (2010)
  • Author(s): Nagai S, Takahashi T, Kurokawa M.
  • Journal Title: Current Stem Cell Research and Therapy (in press)
  • Peer Reviewed
• [Journal Article] Complete molecular remission in refractory acute myeloid leukemia with MLL/AF9 treated with gemtuzumab ozogamicin. (2010)
  • Author(s): Asano H, Yamamoto G, Hosoi M, Takahashi T, Hangaishi A, Kurokawa M.
  • Journal Title: Leukemia Research (in press)
  • Peer Reviewed
• [Journal Article] Jumping translocation involving lq21 during long-term complete remission of acute myeloid leukemia. (2010)
  • Author(s): Nagai S, Nannya Y, Takahashi T, Kurokawa M.
  • Journal Title: Annals of Hematology (in press)
  • Peer Reviewed
• [Journal Article] Blimp-1 is a tumor suppressor gene in lymphoid malignancies. (2010)
  • Author(s): Hangaishi A, Kurokawa M.
  • Journal Title: International Journal of Hematology 91 Pages: 46-53
  • Peer Reviewed
• [Journal Article] Hes1 immortalizes committed progenitors and plays a role in blast crisis transition in chronic myelogenous leukemia. (2010)
  • Author(s): Nakahara F, Sakata-Yanagimoto M, Komeno Y, Kato N, Uchida T, Haraguchi K, Kumano K, Harada Y, Harada H, Kitaura J, Ogawa S, Kurokawa M, Kitamura T, Chiba S.
  • Journal Title: Blood 115 Pages: 2872-2881
  • Peer Reviewed
• [Journal Article] Risk-adapted maintenance therapy for acute promyelocytic leukemia. (2010)
  • Author(s): Nagai S, Takahashi T, Kurokawa M.
  • Journal Title: Journal of Clinical Oncology 28 Pages: e21
  • Peer Reviewed
• [Journal Article] EVI-1 interacts with histone methyltransferases SUV39H1 and G9a for transcriptional repression and bone marrow immortalization. (2010)
  • Author(s): Goyama S, Nitta E, Yoshino T, Kako S, Watanabe-Okochi N, Shimabe M, Imai Y, Takahashi K, Kurokawa M.
  • Journal Title: Leukemia 24 Pages: 81-88
  • Peer Reviewed
• [Journal Article] Molecular or cytogenetic monitoring and preemptive therapy for centralnervous system relapse of acute promyelocytic leukemia. (2010)
  • Author(s): Nagai S, Nannya Y, Arai S, Yoshiki Y, Takahashi T, Kurokawa M.
  • Journal Title: Haematologica 95 Pages: 169-171
  • Peer Reviewed
• [Journal Article] A novel MLL-AF1p/Eps15 fusion variant in therapy-related acute lymphoblastic leukemia, lacking the EH-domains. (2010)
  • Author(s): Shinohara A, Ichikawa M, Ueda K, Takahashi T, Hangaishi A, Kurokawa M.
  • Journal Title: Leukemia Research 34 Pages: e62-3
  • Peer Reviewed
• [Journal Article] The role of Runx1/AML1 and Evi-1 in the regulation of hematopoietic stem cells. (2010)
  • Author(s): Kumano K, Kurokawa M.
  • Journal Title: The Journal of Cellular Physiology 222 Pages: 282-285
  • Peer Reviewed
• [Journal Article] Dual antitumor mechanisms of Notch signaling inhibitor in a T cell acute lymphoblastic leukemia xenograft model. (2009)
  • Author(s): Masuda S, Kumano K, Suzuki T, Tomita T, Iwatsubo T, Natsugari H, Tojo A, Shibutani M, Mitsumori K, Hanazono Y, Ogawa S, Kurokawa M, Chiba S.
  • Journal Title: Cancer Science 100 Pages: 2444-2450
  • Peer Reviewed
• [Journal Article] Arsenic-induced pericardial and pleural effusion without acute promyelocytic leukemia differentiation syndrome. (2009)
  • Author(s): Ueda K, Nagai S, Miyashita S, Kaise T, Ichikawa M, Kumano K, Hangaishi A, Nannya Y, Kurokawa M.
  • Journal Title: Leukemia Research 34 Pages: e25-26
  • Peer Reviewed
• [Journal Article] Pbx1 is a downstream target of Evi-1 in hematopoietic stem/progenitors and leukemic cells. (2009)
  • Author(s): Shimabe M, Goyama S, Watanabe-Okochi N, Yoshimi A, Ichikawa M, Imai Y, Kurokawa M.
  • Journal Title: Oncogene 10 Pages: 4364-4374
  • Peer Reviewed
• [Journal Article] Notch activation induces the generation of functional natural killer cells from human cord blood CD34-positive cells devoid of interleukin-151. (2009)
  • Author(s): Haraguchi K, Suzuki T, Koyama N, Kumano K, Nakahara F, Matsumoto A, Yokoyama Y, Sakata-Yanagimoto M, Masuda S, Takahashi T, Kamijo A, Takahashi K, Takanashi M, Okuyama Y, Yasutomo K, Sakano S, Yagita H, Kurokawa M, Ogawa S, Chiba S.
  • Journal Title: The Journal of Immunology 15 Pages: 6186-6178
  • Peer Reviewed
• [Journal Article] NEDD9 is required for activation of oncogenic signaling pathways in mammary tumor development. (2009)
  • Author(s): Izumchenko E, Plotnikova O, Singh M, Tikhmyanova N, Little J, Seo S, Kurokawa M, Egleston B, Klein-Szanto AJ, Pugacheva E, Hardy R, Connolly D, Wolfson M, Golemis E.
  • Journal Title: Cancer Research 15 Pages: 7198-7206
  • Peer Reviewed
• [Journal Article] Beneficial and adverse effects of molecularly targeted therapies for acute promyelocytic leukemia in central nervous system. (2009)
  • Author(s): Nagai S, Takahashi T, Kurokawa M.
  • Journal Title: CNS and Neurological Disorders-Drug Targets 8 Pages: 387-392
  • Peer Reviewed
• [Journal Article] Derivation of functional mature neutrophils from human embryonic stem cells. (2009)
  • Author(s): Yokoyama Y, Suzuki T, Sakata-Yanagimoto M, Kumano K, Higashi K, Takato T, Kurokawa M, Ogawa S, Chiba S.
  • Journal Title: Blood 113 Pages: 6584-6592
  • Peer Reviewed
• [Journal Article] Gain-of-function mutations and copy number increases of Notch2 in diffuse large B-cell lymphoma. (2009)
  • Author(s): Lee SY, Kumano K, Nakazaki K, Sanada M, Matsumoto A, Yamamoto G, Nannya Y, Suzuki R, Ota S, Ota Y, Izutsu K, Sakata-Yanagimoto M, Hangaishi A, Yagita H, Fukayama M, Seto M, Kurokawa M, Ogawa S, Chiba S.
  • Journal Title: Cancer Science 100 Pages: 920-926
  • Peer Reviewed
• [Presentation] The pathogenesis and novel therapeutics of myelodysplastic syndrome. (2009)
  • Author(s): Kurokawa M.
  • Organizer: The 68^<th> Annual Meeting of the Japanese Cancer Association
  • Place of Presentation: 横浜
  • Year and Date: 2009-10-03
• [Presentation] Deregulated transcription factors in leukemia and MDS (2009)
  • Author(s): 黒川峰夫
  • Organizer: The Korean AML/MDS Working Party Symposium
  • Place of Presentation: 韓国
  • Year and Date: 2009-05-30