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

• Project/Area Number: 16K09871
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Osaka University
• Principal Investigator: SHIBAYAMA HIROHIKO 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)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• 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 / コンディショナルノックアウトマウス / Tリンパ球 / アポトーシス / p38MAPK / B リンパ球 / T リンパ球 / 免疫学 / リンパ球 / 鉄硫黄クラスター蛋白

Outline of Final Research Achievements

Anamorsin (AM), an anti-apoptotic molecule, which we have identified was revealed to be the molecule that works related to iron-sulfur (Fe-S) proteins biosynthesis. In order to clarify the functions of AM in the various cells in vivo and the Fe-S cluster proteins which play important roles in those cells, we produced the AM conditional knock out mice (AM Flox/Flox mice). In this study, we mated CD19 Cre Tg mice with AM Flox/Flox mice to produce B lymphocytes specific AM deficient mice, and analyzed the phenotypes of these mice. We found that the number of the terminal differentiated B lymphocytes (FOLI cells) was markedly decreased in those mice. Furthermore, we found that the expression of P38MAPK was remarkably decreased in both mRNA and protein levels in the AM deficient FOLI cells. From those results, it was shown that AM regulates the expression of P38MAPK in the terminal differentiated B lymphocytes (FOLI cells).

Academic Significance and Societal Importance of the Research Achievements

鉄・硫黄（Fe-S)クラスター分子の形成にアナモルシン（AM）は必須の分子である。興味深いことに細胞種ごとでAMが関連するFe-Sクラスター分子は異なっており、それらを明らかにすることは、AMを標的とした薬剤の開発に寄与すると考えられる。本研究では、遺伝子改変マウスを用いることでBリンパ球の分化・増殖においては、AMはP38MAPKの発現に強く関わっていることが明らかとなった。P38MAPKはシグナル伝達分子の一つだが、AMが欠損すると、その発現が低下し、Bリンパ球の分化が停止することが明らかとなったことで、AMを標的とした薬剤でBリンパ球の分化を制御できる可能性が示された。

Research Products

• [Journal Article] Variable SATB1 Levels Regulate Hematopoietic Stem Cell Heterogeneity with Distinct Lineage Fate (2018)
  • Author(s): Yukiko Doi, Takafumi Yokota, Yusuke Satoh, Daisuke Okuzaki, Masahiro Tokunaga, Tomohiko Ishibashi, Takao Sudo, Tomoaki Ueda, Yasuhiro Shingai, Michiko Ichii, Akira Tanimura, Sachiko Ezoe, Hirohiko Shibayama, Terumi Kohwi-Shigematsu, Junji Takeda, Kenji Oritani, and Yuzuru Kanakura
  • Journal Title: Cell Reports Volume: 23 Issue: 11 Pages: 3223-3235
  • DOI: 10.1016/j.celrep.2018.05.042
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Retrospective analysis of primary plasma cell leukemia in Kansai Myeloma Forum registry (2018)
  • Author(s): Nakaya A, Yagi H, Kaneko H, Kosugi S, Kida T, Adachi Y, Shibayama H, Kohara T, Kamitsuji Y, Fuchida SI, Uoshima N, Kawata E, Uchiyama H, Shimura Y, Takahashi T, Urase F, Ohta K, Hamada T, Miyamoto K, Kobayashi M, Shindo M, Tanaka H, Shimazaki C, Hino M, Kuroda J, Kanakura Y, Takaoari-Kondo A, Nomura S, Matsumura I
  • Journal Title: Leukemia Research Reports Volume: 10 Pages: 7-10
  • DOI: 10.1016/j.lrr.2018.07.001
  • Peer Reviewed / Open Access
• [Journal Article] Identification of MS4A3 as a reliable marker for early myeloid differentiation in human hematopoiesis. (2018)
  • Author(s): Ishibashi T, Yokota T, Satoh Y, Ichii M, Sudo T, Doi Y, Ueda T, Nagate Y, Hamanaka Y, Tanimura A, Ezoe S, Shibayama H, Oritani K, Kanakura Y.
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 495 Issue: 3 Pages: 2338-2343
  • DOI: 10.1016/j.bbrc.2017.12.117
  • Peer Reviewed / Open Access
• [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 Issue: 5 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 Y, Kuroda J, Kaneko H, Kamitsuji Y, Fuchida SI, Nakaya A, Shibayama H, Uoshima N, Yokota I, Uchiyama H, Yagi H, Kosugi S, Matsui T, Ishikawa J, Matsuda M, Ohta K, Iida M, Tanaka H, Kobayashi M, Wada K, Shimazaki C, Nomura S, Imada K, Hino M, Matsumura I, Kanakura Y, Takaori-Kondo A; KMF
  • Journal Title: International Journal of Hematology Volume: 107 Issue: 5 Pages: 541-550
  • DOI: 10.1007/s12185-018-2416-4
  • Peer Reviewed / Open Access
• [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 M, Kashiwagi H, Nakayama K, Sakuragi M, Nakao M, Morikawa T, Kiyokawa T, Aochi H, Nagamine K, Shibayama H, Tomiyama Y.
  • Journal Title: Transfusion Volume: 58 Issue: 12 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 M, Imagawa J, et al.
  • Journal Title: Clin Lymphoma Myeloma Leuk. Volume: 18 Issue: 5 Pages: 353-360
  • DOI: 10.1016/j.clml.2018.03.004
  • NAID: 120006463738
  • Peer Reviewed / Open Access
• [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 Issue: 10 Pages: 3209-3215
  • DOI: 10.1111/cas.13739
  • Peer Reviewed / Open Access
• [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 Issue: 1 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
• [Presentation] コンディショナルノックアウトマウスを用いた抗アポトーシス分子アナモルシンの成体造血での役割の解析 (2017)
  • Author(s): 谷村朗、柴山浩彦、倉重隆明、濱中有理、新開泰宏、西東秀晃、戸田淳、上田智朗、長手泰宏、土居由貴子、一井倫子、横田貴史、江副幸子、金倉譲
  • Organizer: 第79回日本血液学会学術集会
• [Presentation] Anamorsin plays important roles in B-cell development (2016)
  • Author(s): 濱中有理， 柴山浩彦, 谷村朗, 横田貴史, 江副幸子, 一井倫子, 石橋知彦, 土居由貴子, 長手泰宏, 織谷健司, 金倉譲
  • Organizer: 第78回日本血液学会学術集会
  • Place of Presentation: パシフィコ横浜, 神奈川
  • Year and Date: 2016-10-14
• [Presentation] Anamorsin is essential for B-cell terminal differentiation. (2016)
  • Author(s): Hamanaka Y, Shibayama H, Tanimura A, Yokota T, Ezoe S, Ichii M, Ishibashi T, Doi Y, Nagate Y, Oritani K, Kanakura Y
  • Organizer: 21st Congress of European Hematology Association
  • Place of Presentation: The Bella Center, Copenhagen, Denmark
  • Year and Date: 2016-06-11
  • Int'l Joint Research