難治性造血器腫瘍の分子病態と治療標的の解明

2011 Fiscal Year Annual Research Report

• Project/Area Number: 19679004
• Research Institution: The University of Tokyo
• Principal Investigator: 黒川 峰夫 東京大学, 医学部附属病院, 教授 (80312320)
• Keywords: 白血病 / Evi-1 / Runx1 / NF-κB

Research Abstract

われわれはこれまでに、難治性白血病遺伝子Evi-1がポリコームタンパク質と協調して白血病遺伝子として働くことを報告している。今回われわれは、Evi-1高発現白血病発症モデルを用いて、Evi-1による白血病発症を促進する協調因子を探索した。その結果、Evi-1高発現白血病では高頻度にC/EBPbetaが高発現していることがわかった。C/EBPbetaの3つのアイソフォームのうちLIPだけがEvi-1との協調により白血病発症を促進させることもわかった(投稿中)。この知見から、Evi-1とLIPとの機能的な協調関係が、Evi-1高発現白血病を治療する上での新しい治療標的になりうることが示唆された。
われわれは以前樹立した条件的Runx1欠失マウスを用いて、臨床的に高頻度に見られるRunx1機能喪失型変異の白血病細胞における意義を解析した。その結果、MLLキメラ遺伝子白血病モデルにおいて、Runx1が欠失すると白血病細胞の増殖が亢進すること、それにはp19(ARF)の抑制が関係していることがわかった(Nishimoto N, et al. Blood 118:2541-50,2011)。p19(ARF)はp53の制御因子の一つである主要な癌抑制遺伝子であり、Runx1変異による造腫瘍性獲得機構の一端が明らかになった。さらにわれわれは、上記のマウスを用いた網羅的遺伝子発現解析の結果、Runx1の欠失によってNF-κBシグナルが活性化することを見出した。Runx1タンパク質は細胞質でNF-κBシグナルを阻害しており、Runx1変異体ではその機能が失われることがわかった(Nakagawa M et al. Blood 118:6626-37,2011)。この結果から、Runx1変異を有する白血病においてNF-κBシグナルが有望な治療標的である可能性が示唆された。

Research Products

• [Journal Article] The first case of blastic plasmacytoid dendritic cell neoplasm with MLL-ENL rearrangement (2012)
  • Author(s): Toya T, Nishimoto N, Koya J, Nakagawa M, Nakamura F, Kandabashi K, Yamamoto G, Nannya Y, Ichikawa M, Kurokawa M
  • Journal Title: Leukemia Research Volume: 36 Pages: 117-118
  • DOI: 10.1016/j.leukres.2011.07.029
  • Peer Reviewed
• [Journal Article] AML1/RUNX1 functions as a cytoplasmic attenuator of NF-κB signaling in the repression of myeloid tumors (2011)
  • Author(s): 黒川峰夫, 他
  • Journal Title: Blood Volume: 118 Pages: 6626-6633
  • DOI: DOI:10.1182/blood-2010-12-326710
  • Peer Reviewed
• [Journal Article] Related transplantation with HLA-1 Ag mismatch in the GVH direction and HLA-8/8 allele-matched unrelated transplantation : a nationwide retrospective study (2011)
  • Author(s): Kanda J, Saji H, Fukuda T, Kobayashi T, Miyamura K, Eto T, Kurokawa M, Kanamori H, Mori T, Hidaka M, Iwato K, Yoshida T, Sakamaki H, Tanaka J, Kawa K, Morishima Y, Suzuki R, Atsuta Y, Kanda Y
  • Journal Title: Blood Volume: 119 Pages: 2409-2416
  • DOI: 10.1182/blood-2011-08-372573
  • Peer Reviewed
• [Journal Article] The effect of iron overload and chelation on erythroid differentiation (2011)
  • Author(s): Taoka K, Kumano K, Nakamura F, Hosoi M, Goyama S, Imai Y, Hangaishi A, Kurokawa M
  • Journal Title: International Journal of Hematology Volume: 95 Pages: 149-159
  • DOI: 10.1007/s12185-011-0988-3
  • Peer Reviewed
• [Journal Article] Crk-associated substrate lymphocyte type regulates myeloid cell motility and suppresses the progression of leukemia induced by p210Bcr/Abl (2011)
  • Author(s): Seo S, Nakamoto T, Takeshita M, Lu J, Sato T, Suzuki T, Kamikubo Y, Ichikawa M, Noda M, Ogawa S, Honda H, Oda H, Kurokawa M
  • Journal Title: Cancer Science Volume: 102 Pages: 2109-2117
  • DOI: 10.1111/j.1349-7006.2011.02066.x
  • Peer Reviewed
• [Journal Article] Evi1 is essential for hematopoietic stem cell self-renewal, and its expression marks hematopoietic cells with long-term multilineage repopulating activity (2011)
  • Author(s): Kataoka K, Sato T, Yoshimi A, Goyama S, Tsuruta T, Kobayashi H, Shimabe M, Arai S, Nakagawa M, Imai Y, Kumano K, Kumagai K, Kubota N, Kadowaki T, Kurokawa M
  • Journal Title: Journal of Experimental Medicine Volume: 208 Pages: 2403-2416
  • DOI: 10.1084/jem.20110447
  • Peer Reviewed
• [Journal Article] Loss of AML1/Runx1 accelerates the development of MLL-ENL leukemia through down-regulation of p19ARF (2011)
  • Author(s): Nishimoto N, Arai S, Ichikawa M, Nakagawa M, Goyama S, Kumano K, Takahashi T, Kamikubo Y, Imai Y, Kurokawa M
  • Journal Title: Blood Volume: 118 Pages: 2541-2550
  • DOI: 10.1182/blood-2010-10-315440
  • Peer Reviewed
• [Journal Article] Temozolomide may induce therapy-related acute lymphoblastic leukaemia (2011)
  • Author(s): Ogura M, Todo T, Tanaka M, Nannya Y, Ichikawa M, Nakamura F, Kurokawa M
  • Journal Title: British Journal of Haematology Volume: 154 Pages: 663-665
  • DOI: 10.1111/j.1365-2141.2011.08641.x
  • Peer Reviewed
• [Journal Article] Hyperbilirubinemia after hematopoietic stem cell transplantation : comparison of clinical and pathologic findings in 41 autopsied cases (2011)
  • Author(s): Kagoya Y, Takahashi T, Nannya Y, Shinozaki A, Ota S, Fukayama M, Kurokawa M
  • Journal Title: Clinical Transplantation Volume: 25 Pages: E552-E557
  • DOI: 10.1111/j.1399-0012.2011.01498.x
  • Peer Reviewed
• [Journal Article] Evi1 forms a bridge between the epigenetic machinery and signaling pathways (2011)
  • Author(s): Yoshimi A, Kurokawa M
  • Journal Title: Oncotarget Volume: 2 Pages: 575-586
  • Peer Reviewed
• [Journal Article] Nilotinib as frontline therapy for patients with newly diagnosed Ph+ chronic myeloid leukemia in chronic phase : results from the Japanese subgroup of ENESTnd (2011)
  • Author(s): Nakamae H, Shibayama H, Kurokawa M, Fukuda T, Nakaseko C, Kanda Y, Nagai T, Ohnishi K, Maeda Y, Matsuda A, Amagasaki T, Yanada M
  • Journal Title: International Journal of Hematology Volume: 93 Pages: 624-632
  • DOI: 10.1007/s12185-011-0841-8
  • Peer Reviewed
• [Journal Article] The negative impact of female donor/male recipient combination in allogeneic hematopoietic stem cell transplantation depends on disease risk (2011)
  • Author(s): Nannya Y, Kataoka K, Hangaishi A, Imai Y, Takahashi T, Kurokawa M
  • Journal Title: Transplant International Volume: 24 Pages: 469-476
  • DOI: 10.1111/j.1432-2277.2011.01229.x
  • Peer Reviewed
• [Journal Article] Incidence, risk factors and outcomes of bronchiolitis obliterans after allogeneic stem cell transplantation (2011)
  • Author(s): Nakaseko C, Ozawa S, Sakaida E, Sakai M, Kanda Y, Oshima K, Kurokawa M, Takahashi S, Ooi J, Shimizu T, Yokota A, Yoshiba F, Fujimaki K, Kanamori H, Sakai R, Saitoh T, Sakura T, Maruta A, Sakamaki H, Okamoto S
  • Journal Title: International Journal of Hematology Volume: 93 Pages: 375-382
  • DOI: 10.1007/s12185-011-0809-8
  • Peer Reviewed
• [Journal Article] Nilotinib-induced hypothyroidism in a patient with chronic myeloid leukemia (2011)
  • Author(s): Yoshizato T, Nannya Y, Yoshiki Y, Nakamura F, Imai Y, Ichikawa M, Kurokawa M
  • Journal Title: International Journal of Hematology Volume: 93 Pages: 400-402
  • DOI: 10.1007/s12185-011-0790-2
  • Peer Reviewed
• [Journal Article] A case of myeloid sarcoma with correlation to JAK2V617F mutation, complicated by myelofibrosis and secondary acute myeloid leukemia (2011)
  • Author(s): Yoshiki Y, Asai T, Ichikawa M, Hangaishi A, Ota S, Imai Y, Takahashi T, Kurokawa M
  • Journal Title: Internal Medicine Volume: 50 Pages: 2649-2652
  • DOI: 10.2169/internalmedicine.50.5783
  • Peer Reviewed
• [Journal Article] Hepatocellular carcinoma in cirrhotic liver with graft-versus-host disease
  • Author(s): Yoshimi A, Yamamoto G, Goto T, Koike K, Kurokawa M
  • Journal Title: Annals of Hematology Volume: (In press)
  • DOI: 10.1007/s00277-012-1416-3
  • Peer Reviewed
• [Presentation] Molecular pathogenesis and therapeutic targets of hematological malignancies (2011)
  • Author(s): 黒川峰夫
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場(愛知)(招待講演)
  • Year and Date: 2011-10-05