白血病予後を司るNPM1とETS遺伝子MEFとの相互作用の解明

2010 Fiscal Year Annual Research Report

• Project/Area Number: 22591040
• Research Institution: Nagasaki University
• Principal Investigator: 宮崎 泰司 長崎大学, 医歯薬学総合研究科, 教授 (40304943)
• Keywords: ETS遺伝子 / MEF / ELF4 / NPM1 / 急性骨髄性白血病 / 遺伝子変異 / 転写因子

Research Abstract

ETSファミリーに属し転写活性能を持つMEFと急性骨髄性白血病(AML)で最も高頻度に変異の見られるNPM1遺伝子産物との相互作用を調べるために、まず両者の結合を検討した。MEF, NPM1それぞれのcDNAを発現ベクターに挿入後、293T細胞に発現させた。それぞれのtagに対する抗体を用いて免疫沈降を実施し、両者が同一蛋白複合体に存在することが明らかとなった。さらに、in vitro translationによって両蛋白を合成し、その結合を確認できたことより両者がおそらく直接結合していると考えられた。NPM1蛋白によるMEF転写活性の変化を調べるためにIL-3プロモータの既知のMEF結合サイトを組み込んだルシフェラーゼレポーターを作成し、これとともにMEFとNPM1または変異NPM1発現プラスミドを293T細胞に導入し、MEF活性の変化を調べた。その結果、NPM1を発現させるとMEFによる転写活性は低下し、変異NPM1を発現させるとMEF活性はかえって上昇した。細胞溶出液を分画してWestern blot解析を行ったところ、NPM1は既報の通り野生型では核内に存在したが変異によって細胞質で同定されるようになった。しかし、MEFはNPM1変異の有無にかかわらず核内にのみ存在していた。このことより、NPM1変異の有無によるMEF活性能の変化は、その細胞内局在の変化によるものではないと考えられた。これまで、変異NPM1を有するAMLを特徴付ける分子機能の変化は明らかになっていないが、この研究によってNPM1変異による転写因子MEFの活性が上昇することが明らかとなった。

Research Products

• [Journal Article] Pre-transplant imatinib-based therapy improves the outcome of allogeneic hematopoietic stem cell transplantation for BCR-ABL-positive acute lymp hoblastic leukemia. (2011)
  • Author(s): Mizuta S, Matsuo K, Yagasaki F, Yujiri T, Hatta Y, Kimura Y, Ueda Y, Kanamori H, Usui N, Akiyama H, Miyazaki Y, Ohtake S, Atsuta Y, Sakamaki H, Kawa K, Morishima Y, Ohnishi K, Naoe T, Ohno R.
  • Journal Title: Leukemia Volume: Vol.25 Pages: 41-47
  • Peer Reviewed
• [Journal Article] Risk of Myelodysplastic Syndromes in People Exposed to Ionizing Radiation : a Retrospective Cohort Study of Nagasaki Atomic Bomb Survivors. (2011)
  • Author(s): Iwanaga M, Hsu WL, Soda M, Takasaki Y, Tawara M, Joh T, Amenomori A, Yamamura M, Yoshida Y, Koba T, Miyazaki Y, Matsuo T, Preston DL, Suyama A, Kodama K, Tomonaga M.
  • Journal Title: J Clin Oncol Volume: Vol.29 Pages: 428-434
  • Peer Reviewed
• [Journal Article] High expression of 67-kDa laminin receptor relates to the proliferation of leukemia cells and increases expression of GM-CSF receptor. (2011)
  • Author(s): Ando K, Miyazaki Y, Sawayama Y, Tominaga S, Matsuo E, Yamasaki R, Inoue Y, Iwanaga M, Imanishi D, Tsushima H, Fukushima T, Imaizumi Y, Taguchi J, Yoshida S, Hata T, Tomonaga M
  • Journal Title: Exp Hematol Volume: Vol.39 Pages: 179-186, e4
  • Peer Reviewed
• [Journal Article] A decision analysis of allogeneic hematopoietic stem cell transplantation in adult patients with Philadelphia chromosome-negative acute lymphoblastic leukemia in first remission who have an HLA-matched sibling donor. (2011)
  • Author(s): Kako S, Morita S, Sakamaki H, Ogawa H, Fukuda T, Takahashi S, Kanamori H, Onizuka M, Iwato K, Suzuki R, Atsuta Y, Kyo T, Sakura T, Jinnai I, Takeuchi J, Miyazaki Y, Miyawaki S, Ohnishi K, Naoe T, Kanda Y
  • Journal Title: Leukemia. Volume: Vol.25 Pages: 259-265
  • Peer Reviewed
• [Journal Article] Randomized study of induction therapy comparing standard-dose idarubicin with high-dose daunorubicin in adult patients with previously untreated acute myeloid leukemia : JALSG AML201 Study. (2011)
  • Author(s): Ohtake S, Miyawaki S, Fujita H, Kiyoi H, Shinagawa K, Usui N, Okumura H, Miyamura K, Nakaseko C, Miyazaki Y, Fujieda A, Nagai T, Yamane T, Taniwaki M, Takahashi M, Yagasaki F, Kimura Y, Asou N, Sakamaki H, Handa H, Honda S, Ohnishi K, Naoe T, Ohno R.
  • Journal Title: Blood Volume: Vol.117 Pages: 2358-2365
  • Peer Reviewed
• [Journal Article] A randomized comparison of four courses of standard-dose multiagent chemotherapy versus three courses of high-dose cytarabine alone in post-remission therapy for acute myeloid leukemia in adults : the JALSG AML201 study. (2011)
  • Author(s): Miyawaki S, Ohtake S, Fujisawa S, Kiyoi H, Shinagawa K, Usui N, Sakura T, Miyamura K, Nakaseko C, Miyazaki Y, Fujieda A, Nagai T, Yamane T, Taniwaki M, Takahashi M, Yagasaki F, Kimura Y, Asou N, Sakamaki H, Handa H, Honda S, Ohnishi K, Naoe T, Ohno R
  • Journal Title: Blood. Volume: Vol.117 Pages: 2366-2372
  • Peer Reviewed
• [Journal Article] Overexpression of enhancer of zeste homolog 2 with trimethylation of lysine 27 on histone H3 in adult T-cell leukemia/lymphoma as a target for epigenetic therapy. (2011)
  • Author(s): Sasaki D, Imaizumi Y, Hasegawa H, Osaka A, Tsukasaki K, Choi YL, Mano H, Marquez V, Hayashi T, Yanagihara K, Moriwaki Y, Miyazaki Y, Kamihira S, Yamada Y
  • Journal Title: Haematologica Volume: (In Printed)
  • Peer Reviewed
• [Journal Article] Long-term study of indolent adult T-cell leukemia-lymphoma (ATL). (2010)
  • Author(s): Takasaki Y, Iwanaga M, Imaizumi Y, Tawara M, Joh T, Kohno T, Yamada Y, Kamihira S, Ikeda S, Miyazaki Y, Tomonaga M, Tsukasaki K
  • Journal Title: Blood Volume: Vol.115 Pages: 4337-4343
  • Peer Reviewed
• [Journal Article] Array-based genomic resequencing of human leukemia. (2010)
  • Author(s): Yamashita Y, Yuan J, Suetake I, Suzuki H, Ishikawa Y, Choi Y L, Ueno T, Soda M, Hamada T, Haruta H, Takada S, Miyazaki Y, Kiyoi H, Ito E, Naoe T, Tomonaga M, Toyota M, Tajima S, Iwama A, Mano H.
  • Journal Title: Oncogene. Volume: Vol.29 Pages: 3723-3731
  • Peer Reviewed
• [Journal Article] Imatinib for newly diagnosed chronic-phase chronic myeloid leukemia : results of a prospective study in Japan. (2010)
  • Author(s): Nagai T, Takeuchi J, Dobashi N, Kanakura Y, Taniguchi S, Ezaki K, Nakaseko C, Hiraoka A, Okada M, Miyazaki Y, Motoji T, Higashihara M, Tsukamoto N, Kiyoi H, Nakao S, Shinagawa K, Ohno R, Naoe T, Ohnishi K, Usui N
  • Journal Title: Int J Hematol Volume: Vol.92 Pages: 111-117
  • Peer Reviewed
• [Journal Article] Differences in the distribution of subtypes according to the WHO classification 2008 between Japanese and German patients with refractory anemia according to the FAB classification in myelodysplastic syndromes. (2010)
  • Author(s): Matsuda A, Germing U, Jinnai I, Araseki K, Kuendgen A, Strupp C, Iwanaga M, Miyazaki Y, Hata T, Bessho M, Gattermann N, Tomonaga M
  • Journal Title: Leuk Res Volume: Vol.34 Pages: 974-980
  • Peer Reviewed
• [Journal Article] Transplantation of allogeneic hematopoietic stem cells for adult T-cell leukemia : a nationwide retrospective study. (2010)
  • Author(s): Hishizawa M, Kanda J, Utsunomiya A, Taniguchi S, Eto T, Moriuchi Y, Tanosaki R, Kawano F, Miyazaki Y, Masuda M, Nagafuji K, Hara M, Takanashi M, Kai S, Atsuta Y, Suzuki R, Kawase T, Matsuo K, Nagamura-Inoue T, Kato S, Sakamaki H, Morishima Y, Okamura J, Ichinohe T, Uchiyama T
  • Journal Title: Blood Volume: Vol.116 Pages: 1369-1376
  • Peer Reviewed
• [Journal Article] Intensified consolidation therapy with dose-escalated doxorubicin did not improve the prognosis of adults with acute lymphoblastic leukemia : the JALSG-ALL97 study. (2010)
  • Author(s): Jinnai I, Sakura T, Tsuzuki M, Maeda Y, Usui N, Kato M, Okumura H, Kyo T, Ueda Y, Kishimoto Y, Yagasaki F, Tsuboi K, Horiike S, Takeuchi J, Iwanaga M, Miyazaki Y, Miyawaki S, Ohnishi K, Naoe T, Ohno R.
  • Journal Title: Int J Hematol Volume: Vol.92 Pages: 490-502
  • Peer Reviewed
• [Journal Article] Correlation Between Imatinib Pharmacokinetics and Clinical Response in Japanese Patients With Chronic-Phase Chronic Myeloid Leukemia. (2010)
  • Author(s): Takahashi N, Wakita H, Miura M, Scott SA, Nishii K, Masuko M, Sakai M, Maeda Y, Ishige K, Kashimura M, Fujikawa K, Fukazawa M, Katayama T, Monma F, Narita M, Urase F, Furukawa T, Miyazaki Y, Katayama N, Sawada K
  • Journal Title: Clin Pharmacol Ther Volume: Vol.88 Pages: 809-813
  • Peer Reviewed
• [Journal Article] AMLに対する分子標的療法の現状と展望 (2010)
  • Author(s): 安東恒史、宮崎泰司
  • Journal Title: 血液・腫瘍科 Volume: 60巻 Pages: 448-453
• [Journal Article] I.白血病の分子標的療法 (2010)
  • Author(s): 宮崎泰司
  • Journal Title: 癌と化学療法 Volume: 37巻 Pages: 806-810
• [Journal Article] [第71回日本血液学会学術集会 シンポジウム1 標準リスク急性白血病第一寛解期の治療選択-移植vs化学療法の臨床決断のための思考過程-]急性骨髄性白血病の場合-JALSGの経験から- (2010)
  • Author(s): 宮崎泰司
  • Journal Title: 臨床血液 Volume: 51巻 Pages: 471-476
  • Peer Reviewed
• [Journal Article] [第11回日本検査血液学会学術集会シンポジウム1 造血器腫瘍の改訂WHO2008分類の特徴と将来展望]2.AML/MDSの分類と新たな治療戦略 (2010)
  • Author(s): 宮崎泰司
  • Journal Title: 日本検査血液学会雑誌 Volume: 11巻 Pages: 364-371
• [Journal Article] 臨床 1 実地診療に役立つ急性白血病の病型分類 (2010)
  • Author(s): 宮崎泰司
  • Journal Title: 治療学 Volume: 44巻 Pages: 1365-1369
• [Presentation] Transcriptional Activity of MEF/ELF4 on the HDM2 Promoter Is Enhanced by the Mutation of the NPM1 Gene. (2010)
  • Author(s): Ando Koji, Matsuo Emi, Horio Kensuke, Tominaga Shinya, Imanishi Daisuke, Imaizumi Yoshitaka, Tsushima Hideki, Iwanaga Masako, Kiyoi Hitoshi, Naoe Tomoki, Miyazaki Yasushi
  • Organizer: 52th American Society of Hematology Annual Meeting and Exposition
  • Place of Presentation: Orando, FL, Orange Country Convention Center USA
  • Year and Date: 2010-12-06
• [Presentation] ATL治療の進歩 (2010)
  • Author(s): 宮崎泰司
  • Organizer: 第42回日本内科学会九州支部主催教育講演会
  • Place of Presentation: 鹿児島大学医学部鶴陵会館(鹿児島県)
  • Year and Date: 2010-11-14
• [Presentation] 骨髄異形成症候群の分子標的治療 (2010)
  • Author(s): 宮崎泰司
  • Organizer: 第48回日本癌治療学会学術集会
  • Place of Presentation: 国立京都国際会館、グランドプリンスホテル京都(京都府)
  • Year and Date: 2010-10-30
• [Presentation] 36month follow-up of a phase I / II study of nilotinib for imatinib-resistant or -intolerant CML-CP. (2010)
  • Author(s): Kazuma Oyashiki, Kensuke Usuki, Arinobu Tojo, Yasuhiro Maeda, Tatsuya Kawaguchi, Akira Matsuda, Yukio Kobayashi, Koichi Miyamura, Akirou Kimura, Yasushi Miyazaki, Taro Amagasaki, Eiji kawahara, Aira Wanajo, Tomoki Naoe
  • Organizer: 第72回日本血液学会学術集会
  • Place of Presentation: パシフィコ横浜(神奈川県)
  • Year and Date: 2010-09-26
• [Presentation] Clinical significance of WT1mRNA expression level in patients with myelodysplastic syndrome(MDS). (2010)
  • Author(s): Yasuhito Nannya, Mineo Kurokawa, Yasunori Ueda, Jin Takeuchi, Hideto Tamura, Kiyoyuki Ogata, Hirohiko Shibayama, Keiko Niimi, Nobuhiko Emi, Toshiko Motoji, KouSasaki, kensuke Usuki, Hiroyasu Ogawa, Toru Sakura, Kazuma Ohyashiki, Keiya Ozawa, Masaharu Kasai, Yasushi Miyazaki, Yasunobu Morita, Akira Matsuda, Kaoru Tohyama, Daisuke Koga, Hiroya Tamaki, Kinuko Mitani, Tomoki Naoe, Haruo Sugiyama, Fumimaro Takaku
  • Organizer: 第72回日本血液学会学術集会
  • Place of Presentation: パシフィコ横浜(神奈川県)
  • Year and Date: 2010-09-26
• [Presentation] Mutation of IDH1 and IDH2 genes in cytogenetically normal acute myeloid leukemia. (2010)
  • Author(s): Hideaki Hoshino, Hitoshi Kiyoi, Syuuichi Miyawaki, Yasushi Miyazaki, Kazutaka Kuriyama, Masao Tomonaga, Tomoki Naoe
  • Organizer: 第72回日本血液学会学術集会
  • Place of Presentation: パシフィコ横浜(神奈川県)
  • Year and Date: 2010-09-25
• [Presentation] Decision analysis of HLA-matched unrelated stem cell transplantation for ALL in first remission. (2010)
  • Author(s): Shinichi Kako, Satoshi Morita, Hisashi Sakamaki, Hiroatsu Iida, Mineo Kurokawa, Koichi Miyamura, Heiwa Kanamori, Masamichi Hara, Naoki Kobayashi, Yasuo Morishima, Keisei Kawa, Taichi Kyo, Toru Sakura, Itsuro Jinnai, Jin Takeuchi, Yasushi Miyazaki, Shuichi Miyawaki, Kazunori Ohnishi, Tomoki Naoe, Yoshinobu Kanda
  • Organizer: 第72回日本血液学会学術集会
  • Place of Presentation: パシフィコ横浜(神奈川県)
  • Year and Date: 2010-09-25
• [Presentation] Coexistence of renal AL amyloidosis and gastrointestinal AA amyloidosis in multiple myeloma patient. (2010)
  • Author(s): Masataka Taguchi, Jun Taguchi, Daisuke Imanishi, Yoshitaka Imaizumi, Tomoko Hata, Takuya Fukushima, Kunihiro Tsukasaki, Yasushi Miyazaki
  • Organizer: 第72回日本血液学会学術集会
  • Place of Presentation: パシフィコ横浜(神奈川県)
  • Year and Date: 2010-09-25
• [Presentation] Prognostic impact of blood transfusion dependency in lower risk MDS patients. (2010)
  • Author(s): Yoriko Inoue, Tomoko Hata, Jun Taguchi, Yoshitaka Imaizumi, Hideki Tsushima, Kazuhiro Nagai, Masao Tomonaga, Yasushi Miyazaki
  • Organizer: 第72回日本血液学会学術集会
  • Place of Presentation: パシフィコ横浜(神奈川県)
  • Year and Date: 2010-09-25
• [Presentation] 急性骨髄性白血病の分子病態と診断 (2010)
  • Author(s): 宮崎泰司
  • Organizer: 第72回日本血液学会学術集会
  • Place of Presentation: パシフィコ横浜(神奈川県)
  • Year and Date: 2010-09-24
• [Presentation] The function of MEF is regulated by NPM1 that participate in leukemogenesis in AML. (2010)
  • Author(s): Koji Ando, Emi Matsuo, Shinya Tominaga, Kensuke Horio, Daisuke Imanishi, Yoshitaka Imaizumi, Hideki Tsushima, Hitoshi Kiyoi, Tomoki Naoe, Yasushi Miyazaki
  • Organizer: 第72回日本血液学会学術集会
  • Place of Presentation: パシフィコ横浜(神奈川県)
  • Year and Date: 2010-09-24
• [Presentation] Progressive metastatic pulmonary calcification associated with adult T-cell leukemia/lymphoma(ATL). (2010)
  • Author(s): Junya Makiyama, Jun Taguchi, Hidehiro Itonaga, Yoshitaka Imaizumi, Daisuke Imanishi, Takuya Fukushima, Tomoko Hata, Kunihiro Tsukasaki, Yasushi Miyazaki, Yuuji Ishimatsu, Tomayoshi Hayashi
  • Organizer: 第72回日本血液学会学術集会
  • Place of Presentation: パシフィコ横浜(神奈川県)
  • Year and Date: 2010-09-24
• [Presentation] BCR-ABL mutation status before and during nilotinib treatment in patients with CML and Ph+ALL. (2010)
  • Author(s): Arinobu Tojo, Kazuma Ohyashiki, Chiaki Nakaseko, Yasushi Miyazaki, Taro Amagasaki, Eiji Kawahara, Masamitsu Yanada, Tomoki Naoe
  • Organizer: 第72回日本血液学会学術集会
  • Place of Presentation: パシフィコ横浜(神奈川県)
  • Year and Date: 2010-09-24
• [Presentation] 骨髄異形成症候群に対する診断と治療の現状 (2010)
  • Author(s): 宮崎泰司
  • Organizer: 第69回日本癌学会学術総会
  • Place of Presentation: 大阪国際会議場・リーガロイヤルホテル大阪(大阪府)
  • Year and Date: 2010-09-22
• [Presentation] AML/MDSの分類と新たな治療戦略 (2010)
  • Author(s): 宮崎泰司
  • Organizer: 第11回日本検査血液学会学術集会
  • Place of Presentation: 東京ビックサイト(東京都)
  • Year and Date: 2010-07-24
• [Book] Annual Review 血液2011 (2011)
  • Author(s): 宮崎泰司
  • Total Pages: 79-83
  • Publisher: (株)中外医学社(東京)
• [Book] 血液疾患最新の治療 2011-2013 (2010)
  • Author(s): 宮崎泰司
  • Total Pages: 131-137
  • Publisher: (株)南江堂(東京)