Clarification of the roles of anamorsin in the lymphocytes differentiation and proliferation

2018 Fiscal Year Annual Research Report

• Project/Area Number: 16K09871
• Research Institution: Osaka University
• Principal Investigator: 柴山 浩彦 大阪大学, 医学系研究科, 准教授 (60346202)
• Co-Investigator(Kenkyū-buntansha): 金倉 譲 大阪大学, 医学系研究科, 教授 (20177489) ; 織谷 健司 大阪大学, 医学系研究科, 准教授 (70324762) [Withdrawn]
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: アナモルシン / 鉄・硫黄クラスター / 遺伝子改変マウス / Bリンパ球 / P38MAPK

Outline of Annual Research Achievements

申請者らが、抗アポトーシス分子としてクローニングしたAnamorsin(AM）は、その後の継続した研究により、鉄・硫黄（Fe-S)クラスターを形成する分子として機能していることが示されている。In vivoでの種々の細胞におけるAMの機能を解析し、それらの細胞において、重要な働きをしているFe-Sクラスター蛋白を明らかにする目的にて、AMコンディショナルノックアウトマウス（AM Flox/Floxマウス）を作製した。本研究では、Bリンパ球、Tリンパ球特異的に、AMを欠損させたマウスを作製し、それらのフェノタイプの解析をおこなった。
Bリンパ球特異的にAMを欠損したマウスを、CD19 Creトランスジェニック（Tg)マウスとAM Flox/Floxマウスを交配し作製したところ、脾臓に局在するFOLⅠの分化段階のBリンパ球が極端に減少していることが明らかとなった。また、その分化段階にて、アポトーシスの亢進がみられることも確認した。その分化段階のAM欠損Bリンパ球と正常Bリンパ球の遺伝子発現の違いをRNA seqをおこない比較し、発現に差のあった分子の中で、Bリンパ球の分化・増殖に関与するシグナル伝達に関わる分子群にしぼって検討したところ、FOLI細胞のみならず、FOLIの前分化段階のT1細胞においても、P38MAPK遺伝子の発現が有意に低下していた。ウェスタンブロット法をおこない、蛋白レベルにおいてもP38MAPKの発現は低下していることが示され、Bリンパ球の最終分化におけるAMの標的蛋白はP38MAPKであることが明らかとなった。P38MAPKの発現は、正常Bリンパ球においても、T1、T2からFOLIに分化する際に、上昇することがわかっており、AMが欠損することで、この発現上昇が抑制されることがFOLI細胞の低下につながっていると考えられた。

Research Products

• [Journal Article] Variable SATB1 Levels Regulate Hematopoietic Stem Cell Heterogeneity with Distinct Lineage Fate (2018)
  • Author(s): Doi Yukiko、Yokota Takafumi、Satoh Yusuke、Okuzaki Daisuke、Tokunaga Masahiro、Ishibashi Tomohiko、Sudo Takao、Ueda Tomoaki、Shingai Yasuhiro、Ichii Michiko、Tanimura Akira、Ezoe Sachiko、Shibayama Hirohiko、Kohwi-Shigematsu Terumi、Takeda Junji、Oritani Kenji、Kanakura Yuzuru
  • Journal Title: Cell Reports Volume: 23 Pages: 3223～3235
  • DOI: 10.1016/j.celrep.2018.05.042
  • Peer Reviewed
• [Journal Article] Retrospective analysis of primary plasma cell leukemia in Kansai Myeloma Forum registry (2018)
  • Author(s): Nakaya Aya、Yagi Hideo、Kaneko Hitomi、Kosugi Satoru、Kida Toru、Adachi Yoko、Shibayama Hirohiko、Kohara Takae、Fuchida Shin-ichi、Uoshima Nobuhiko、Ohta Kensuke、Shimazaki Chihiro、Hino Masayuki、Kuroda Junya、Kanakura Yuzuru、Takaoari-Kondo Akifumi、Nomura Shosaku、Matsumura Itaru
  • Journal Title: Leukemia Research Reports Volume: 10 Pages: 7～10
  • DOI: 10.1016/j.lrr.2018.07.001
  • Peer Reviewed
• [Journal Article] Identification of MS4A3 as a reliable marker for early myeloid differentiation in human hematopoiesis (2018)
  • Author(s): Ishibashi Tomohiko、Yokota Takafumi、Satoh Yusuke、Ichii Michiko、Sudo Takao、Doi Yukiko、Ueda Tomoaki、Nagate Yasuhiro、Hamanaka Yuri、Tanimura Akira、Ezoe Sachiko、Shibayama Hirohiko、Oritani Kenji、Kanakura Yuzuru
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 495 Pages: 2338～2343
  • DOI: 10.1016/j.bbrc.2017.12.117
  • Peer Reviewed
• [Journal Article] Efficacy and safety of switching to nilotinib in patients with CML-CP in major molecular response to imatinib: results of a multicenter phase II trial (NILSw trial) (2018)
  • Author(s): Ishikawa Jun、Matsumura Itaru、Kawaguchi Tatsuya、Kuroda Junya、Nakamae Hirohisa、Miyamoto Toshihiro、Matsuoka Ken-ichi、Shibayama Hirohiko、Hino Masayuki、Hirase Chikara、Kamimura Tomohiko、Shimose Takayuki、Akashi Koichi、Kanakura Yuzuru
  • Journal Title: International Journal of Hematology Volume: 107 Pages: 535～540
  • DOI: 10.1007/s12185-018-2401-y
  • Peer Reviewed
• [Journal Article] Pomalidomide with or without dexamethasone for relapsed/refractory multiple myeloma in Japan: a retrospective analysis by the Kansai Myeloma Forum (2018)
  • Author(s): Matsumura-Kimoto Yayoi、Kansai Myeloma Forum Investigators、Kuroda Junya、Kaneko Hitomi、Fuchida Shin-ichi、Nakaya Aya、Shibayama Hirohiko、Kosugi Satoru、Ishikawa Jun、Ohta Kensuke、Shimazaki Chihiro、Nomura Shosaku、Hino Masayuki、Matsumura Itaru、Kanakura Yuzuru、Takaori-Kondo Akifumi
  • Journal Title: International Journal of Hematology Volume: 107 Pages: 541～550
  • DOI: 10.1007/s12185-018-2416-4
  • Peer Reviewed
• [Journal Article] Distinct effects of daratumumab on indirect and direct antiglobulin tests: a new method employing 0.01 mol/L dithiothreitol for negating the daratumumab interference with preserving K antigenicity (Osaka method) (2018)
  • Author(s): Hosokawa Mika、Kashiwagi Hirokazu、Nakayama Kotarosumitomo、Sakuragi Mikiko、Nakao Mayumi、Morikawa Tamayo、Kiyokawa Tomoko、Aochi Hiroshi、Nagamine Keisuke、Shibayama Hirohiko、Tomiyama Yoshiaki
  • Journal Title: Transfusion Volume: 58 Pages: 3003～3013
  • DOI: 10.1111/trf.14900
  • Peer Reviewed
• [Journal Article] Final 3-year Results of the Dasatinib Discontinuation Trial in Patients With Chronic Myeloid Leukemia Who Received Dasatinib as a Second-line Treatment (2018)
  • Author(s): Okada Masaya、Imagawa Jun、Tanaka Hideo、Nakamae Hirohisa、Hino Masayuki、Sakamaki Hisashi、Wakita Hisashi、Nakagawa Yasunori、Minami Yosuke、Uike Naokuni、Usuki Kensuke、Mizuta Syuichi、Kosugi Hiroshi、Shibayama Hirohiko、Maeda Yasuhiro、Adachi Yoko、Okamoto Takahiro、Nohgawa Masaharu、Yoshihara Satoshi、Kimura Shinya
  • Journal Title: Clinical Lymphoma Myeloma and Leukemia Volume: 18 Pages: 353～360.e1
  • DOI: 10.1016/j.clml.2018.03.004
  • Peer Reviewed
• [Journal Article] Five-day regimen of azacitidine for lower-risk myelodysplastic syndromes (refractory anemia or refractory anemia with ringed sideroblasts): A prospective single-arm phase 2 trial (2018)
  • Author(s): Morita Yasuyoshi、Maeda Yasuhiro、Yamaguchi Terufumi、Urase Fumiaki、Kawata Shuhei、Hanamoto Hitoshi、Tsubaki Kazuo、Ishikawa Jun、Shibayama Hirohiko、Matsumura Itaru、Matsuda Mitsuhiro
  • Journal Title: Cancer Science Volume: 109 Pages: 3209～3215
  • DOI: 10.1111/cas.13739
• [Journal Article] Multicenter phase 1/2 study of forodesine in patients with relapsed peripheral T cell lymphoma (2018)
  • Author(s): Maruyama Dai、Tsukasaki Kunihiro、Uchida Toshiki、Maeda Yoshinobu、Shibayama Hirohiko、Nagai Hirokazu、Hatake Kiyohiko、Ando Kiyoshi、Yoshida Isao、Taniwaki Masafumi、Suzumiya Junji、Tamura Kazuo、Yamauchi Takahiro、Ueda Ryuzo、Tobinai Kensei
  • Journal Title: Annals of Hematology Volume: 98 Pages: 131～142
  • DOI: 10.1007/s00277-018-3418-2
• [Presentation] 抗アポトーシス分子アナモルシンによる細胞内鉄代謝制御 (2018)
  • Author(s): 谷村 朗, 柴山浩彦
  • Organizer: 第42回日本鉄バイオサイエンス学術集会
  • Invited
• [Presentation] 抗アポトーシス分子アナモルシンと血液疾患 (2018)
  • Author(s): 柴山浩彦
  • Organizer: 血液疾患フォーラム in FUKUYAMA
  • Invited
• [Presentation] Brentuximab vedotin plus chemotherapy in high-risk, advanced-stage classical Hodgkin lymphoma patients: Results of pre-specified sub-group analyses from the ECHELON-1 study. (2018)
  • Author(s): Martin Hutchings, John Radford, Andrea Gallamini, Arpad Illes, Anna Sureda, Joseph M. Connors, Alice Sykorova, Hirohiko Shibayama, Jeremy S. Abramson, Neil Chua, Jonathan W. Friedberg, Jan Koren, Ann Steward LaCasce, Lysiane Molina, Neil Josephson, Eric Song, Hina Jolin, Rachael Liu, Ashish Gautam, Stephen Ansell
  • Organizer: 23rd Congress of the European Hematology Association
  • Int'l Joint Research
• [Presentation] Hematopoietic Stem Cell Surface Antigen ESAM Depicts Autonomous Fluctuation of Leukemic Stem Cells Via TGFβ Signaling Pathway. (2018)
  • Author(s): Yasuhiro Shingai, Takafumi Yokota, Takayuki Ozawa, Tomoaki Ueda, Yukiko Doi, Tomohiko Ishibashi,Takao Sudo, Akira Tanimura, Michiko Ichii, Hirohiko Shibayama and Yuzuru Kanakura
  • Organizer: The 9th JSH International Symposium 2018
  • Int'l Joint Research
• [Presentation] Addition of melphalan to fludarabine / busulfan (FLU/BU4/MEL) provides survival benefit for patients with myeloid malignancy following allogeneic bone marrow transplantation/peripheral blood stem cell transplantation. (2018)
  • Author(s): Tomoaki Ueda, Tetsuo Maeda, Kentaro Fukushima, Jiro Fujita, Shinsuke Kusakabe, Takafumi Yokota, Hirohiko Shibayama, Yoshiaki Tomiyama Yuzuru Kanakura
  • Organizer: The American Society of Hematology 60th Annual Meeting
  • Int'l Joint Research
• [Presentation] Ectonucleosidase CD39 Is Highly Expressed on ATLL Cells and Suppresses the Immune Response through theAdenosine Pathway. (2018)
  • Author(s): Yasuhiro Nagate, Sachiko Ezoe, Jiro Fujita, Takafumi Yokota, Michiko Ichii, Akira Tanimura, Yukiko Doi, Tomoaki Ueda, Jun Toda, Hirohiko Shibayama, Kenji Oritani, Yuzuru Kanakura
  • Organizer: The American Society of Hematology 60th Annual Meeting
  • Int'l Joint Research
• [Presentation] A Novel Unifrac-Based Analytical Method for Determining Sequential Changes in Gut Microbiota after Hematopoietic Stem Cell Transplantation. (2018)
  • Author(s): Shinsuke Kusakabe, Kentaro Fukushima, Tetsuo Maeda, Takafumi Yokota, Ritsuko Nakai, Akihisa Hino, Yasuhiro Nagate, Jiro Fujita, Motooka Daisuke, Shota Nakamura, Hirohiko Shibayama, Yuzuru Kanakura
  • Organizer: The American Society of Hematology 60th Annual Meeting
  • Int'l Joint Research
• [Presentation] ESAM on the Cells of Endothelial Lineage Plays an Important Role in the Development of Definitive Hematopoiesis. (2018)
  • Author(s): Tomoaki Ueda, Takafumi Yokota, Yoshihiro Uno, Tomoji Mashimo, Takao Sudo, Tomohiko Ishibashi, Yukiko Doi1, Yasuhiro Shingai, Akira Tanimura, Michiko Ichii, Sachiko Ezoe, Hirohiko Shibayama, Kenji Oritani, Yuzuru Kanakura
  • Organizer: The American Society of Hematology 60th Annual Meeting
  • Int'l Joint Research
• [Presentation] Signal Transducing Adaptor Protein (STAP) Family Accelerates Gut and Thymic Graft-Versus-Host-Disease in Murine Model. (2018)
  • Author(s): Hideaki Saito, Michiko Ichii, Jun Toda, Yuichi Kitai, Ryuta Muromoto, Jun-ichi Kashiwakura, Kodai Saitoh, Hirohiko Shibayama, Tadashi Matsuda, Kenji Oritani, Yuzuru Kanakura
  • Organizer: The American Society of Hematology 60th Annual Meeting
  • Int'l Joint Research