Characteristics of leukemic niche with regard to Mediator transcriptional coregulatory complex

• Project/Area Number: 17K09012
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Laboratory medicine
• Research Institution: Kobe University
• Principal Investigator: Ito Mitsuhiro 神戸大学, 保健学研究科, 教授 (50362794)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: MED1 / 造血ニッチ / MGP / 白血病幹細胞 / メディエーター / Gla化 / 転写コアクチベーター / ビタミンD受容体 / 生体分子 / 生理活性 / 内科 / 発現制御

Outline of Final Research Achievements

Transcription, the mechanism of RNA synthesis from DNA as a template, is dictated by Mediator transcriptional coregulatory complex. The MED1 component of Mediator complex is necessary for appropriate hematopoiesis. In this study, MGP produced by bone marrow stromal cells through MED1 was thought to employ a physiological role in this mechanism. MGP was found to support not only normal, but also malignant, hematopoietic progenitor cells. Thus MGP was proven to be a novel niche factor in hematopoiesis, which, as the first proposal of MGP’s role in hematopoiesis, signifies this study.

Academic Significance and Societal Importance of the Research Achievements

白血病は血液がんであり、抗がん剤治療や骨髄移植等で予後の改善が得られてはいるが、今なお死の転機をとげること多く、また治療もつらい抗がん剤の治療が主体になるものが多い。これらを改善するには新たなアプローチが必要であり、そのためには白血病のみならず正常の造血機構を知る必要がある。本研究で、MGPが造血の支持機構を担うことが初めて証明された。また、正常造血と悪性造血における違いも明らかになった。本研究の先に、MGPを標的とする治療アプローチがありうることを示すものであり、今後の研究の動向に期待したい。

Research Products

• [Int'l Joint Research] ロックフェラー大学(米国)
• [Int'l Joint Research] The Rockefeller University(米国)
• [Int'l Joint Research] ロックフェラー大学(米国)
• [Int'l Joint Research] 台湾国立大学(台湾)
• [Journal Article] Detection of a novel CBFB-MYH11 fusion transcript in acute myeloid leukemia M1 with inv(16)(p13q22). (2020)
  • Author(s): Kurata K, Yamamoto K, Okazaki Y, Noguchi Y, Matsui K, Matsumoto H, Inui Y, Yakushijin K, Ito M, Nakamachi Y, Matsuoka H, Saegusa J, Minami H.
  • Journal Title: Cancer Genet Volume: 241 Pages: 72-76
  • DOI: 10.1016/j.cancergen.2019.07.005
  • NAID: 120006818788
  • Peer Reviewed
• [Journal Article] MYC amplification on double minute chromosomes in plasma cell leukemia with double IGH/CCND1 fusion genes. (2020)
  • Author(s): Yamamoto K, Yakushijin K, Ito M, Goto H, Higashime A, Kajimoto K, Hayashi Y, Matsuoka H, Minami H
  • Journal Title: Cancer Genet Volume: 242 Pages: 35-40
  • DOI: 10.1016/j.cancergen.2020.01.049
  • NAID: 120006823972
  • Peer Reviewed
• [Journal Article] Matrix Gla protein maintains normal and malignant hematopoietic progenitor cells by interacting with bone morphogenetic protein-4 (2020)
  • Author(s): Kana Kuronuma, Aya Yokoi, Tomoya Fukuoka, Muneaki Miyata, Akio Maekawa, Satowa Tanaka, Leo Matsubara, Chie Goto, Miki Matsuo, Hao-Wei Han, Mai Tsuruta, Haruka Murata, Hikari Okamoto, Natsumi Hasegawa, Shigetaka Asano, Mitsuhiro Ito
  • Journal Title: Heliyon Volume: 6 Issue: 4 Pages: 03743-03743
  • DOI: 10.1016/j.heliyon.2020.e03743
  • NAID: 120006844969
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Successful Bridging Chemotherapy with Gemcitabine, Carboplatin, and Dexamethasone before Unrelated Stem Cell Transplantation for Hepatosplenic T-cell Lymphoma (2019)
  • Author(s): Okuni M、Yakushijin K、Uehara K、Ichikawa H、Suto H、Hashimoto A、Tanaka Y、Shinzato I、Sakai R、Mizutani Y、Nagao Si、Kurata K、Kakiuchi S、Miyata Y、Inui Y、Saito Y、Kawamoto S、Yamamoto K、Ito M、Matsuoka H、Minami H
  • Journal Title: Internal Medicine Volume: 58 Issue: 5 Pages: 707-712
  • DOI: 10.2169/internalmedicine.1266-18
  • NAID: 130007606906
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2019-03-01
  • Peer Reviewed / Open Access
• [Journal Article] PML-RARα Induces All-Trans Retinoic Acid-Dependent Transcriptional Activation Through Interaction With MED1 (2019)
  • Author(s): Tomoya Fukuoka, Asami Kawai, Taku Takahara, Mahiro Mori, Robert G Roeder, Natsumi Hasegawa, Mitsuhiro Ito
  • Journal Title: Transcription Volume: 10 Issue: 3 Pages: 147-156
  • DOI: 10.1080/21541264.2019.1624467
  • NAID: 120006653243
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Translin restricts the growth of pubertal mammary epithelial cells estrogen-independently in mice. (2019)
  • Author(s): Matsubara L, Fukuoka T, Sudo K, Fukunaga T, Imanishi A, Kuronuma K, Matsuo M, Kamoshida S, Hasegawa N, Asano S, Ito M.
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 521 Issue: 3 Pages: 562-568
  • DOI: 10.1016/j.bbrc.2019.10.176
  • NAID: 120006784500
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Human herpesvirus 6 encephalitis in patients administered mycophenolate mofetil as prophylaxis for graft-versus-host disease after allogeneic hematopoietic stem cell transplantation (2018)
  • Author(s): Inui Y、Yakushijin K、Okamura A、Tanaka Y、Shinzato I、Nomura T、Ichikawa H、Mizutani Y、Kitao A、Kurata K、Kakiuchi S、Miyata Y、Sanada Y、Kitagawa K、Uryu K、Kawamoto S、Yamamoto K、Matsuoka H、Murayama T、Ito M、Minami H
  • Journal Title: Transplant Infectious Disease Volume: 21 Issue: 1
  • DOI: 10.1111/tid.13024
  • NAID: 120006888556
  • Peer Reviewed / Open Access
• [Journal Article] Translin modulates mesenchymal cell proliferation and differentiation in mice (2018)
  • Author(s): Ikeuchi Yukiko、Imanishi Azusa、Sudo Katsuko、Fukunaga Takako、Yokoi Aya、Matsubara Leo、Goto Chie、Fukuoka Tomoya、Kuronuma Kana、Kono Ruri、Hasegawa Natsumi、Asano Shigetaka、Ito Mitsuhiro
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 504 Issue: 1 Pages: 115-122
  • DOI: 10.1016/j.bbrc.2018.08.141
  • NAID: 120006533204
  • Peer Reviewed
• [Journal Article] Invasive Scopulariopsis alboflavescens infection in patient with acute myeloid leukemia (2018)
  • Author(s): Kurata Keiji、Nishimura Sho、Ichikawa Hiroya、Sakai Rina、Mizutani Yu、Takenaka Kei、Kakiuchi Seiji、Miyata Yoshiharu、Kitao Akihito、Yakushijin Kimikazu、Kawamoto Shinichiro、Yamamoto Katsuya、Ito Mitsuhiro、Matsuoka Hiroshi、Tokimatsu Issei、Kamei Katsuhiko、Minami Hironobu
  • Journal Title: International Journal of Hematology Volume: 108 Issue: 6 Pages: 658-664
  • DOI: 10.1007/s12185-018-2496-1
  • Peer Reviewed
• [Journal Article] Efficacy of Oral Ruxolitinib in a Patient with Refractory Chronic Spontaneous Urticaria (2018)
  • Author(s): Fukunaga A、Ito M、Nishigori C
  • Journal Title: Acta Dermato Venereologica Volume: 98 Issue: 9 Pages: 904-905
  • DOI: 10.2340/00015555-3006
  • NAID: 120006536964
  • Peer Reviewed
• [Journal Article] Early lymphocyte recovery predicts clinical outcome after HSCT with mycophenolate mofetil prophylaxis in the Japanese population. (2018)
  • Author(s): Kurata K, Yakushijin K, Mizuno I, Gomyo H, Okamura A, Ichikawa H, Sakai R, Mizutani Y, Kakiuchi S, Miyata Y, Kitao A, Sanada Y, Inui Y, Uryu K, Kawamoto S, Sugimoto T, Yamamoto K, Ito M, Matsuoka H, Murayama T, Minami H
  • Journal Title: Int J Hematol Volume: 印刷中 Issue: 1 Pages: 58-65
  • DOI: 10.1007/s12185-018-2437-z
  • NAID: 120006621159
  • Peer Reviewed
• [Journal Article] A Case of Classical Hodgkin Lymphoma with Total Lymph Node Infarction (2018)
  • Author(s): Okuni M, Yakushijin K, Sakai Y, Suto H, Ichikawa H, Sakai R, Kakiuchi S, Kurata K, Mizutani Y, Kitao A, Miyata Y, Saito Y, Kawamoto S, Yamamoto K, Ito M, Matsuoka H, Minami H.
  • Journal Title: Journal of Clinical and Experimental Hematopathology Volume: 58 Issue: 1 Pages: 24-26
  • DOI: 10.3960/jslrt.17026
  • NAID: 130006512991
  • ISSN: 1346-4280, 1880-9952
  • Peer Reviewed / Open Access
• [Presentation] Solitary plasmacytoma with unicentric Castleman disease in a 16-year-old patient. (2019)
  • Author(s): Yoko Ishikawa，Keiji Kurata，Kimikazu Yakushijin， Katsuya Yamamoto，Mitsuhiro Ito，Hiroshi Matsuoka，Hitomi Hara， Hikaru Kubota，Daisuke Miyawaki，Toshinori Soejima，Ryohei Sasaki，Tomoo Ito，Hironobu Minami.
  • Organizer: 第81回日本血液学会学術集会
• [Presentation] The interaction of PML-RARα with MED1 initiates ATRA dependent transcriptional activation. (2019)
  • Author(s): Tomoya Fukuoka，Miki Matsuo，Hikaru Tsutsumi，Mana Morikawa， Rino Kishida，Manami Tsuji，Kyo Saiki，Naoya Kanada， Mizuha Anamoto，Natsumi Hasegawa，Mitsuhiro Ito
  • Organizer: 第81回日本血液学会学術集会
• [Presentation] MGP supports niche-dependent myeloid leukemic cells in a Glu γ-carboxylation independent manner. (2019)
  • Author(s): Haruka Murata，Kana Kuronuma，Leo Matsubara，Aya Yokoi， Hikari Okamoto，Mai Tsuruta，Tomoya Fukuoka，Miki Matsuo, Natsumi Hasegawa，Shigetaka Asano，Mitsuhiro Ito
  • Organizer: 第81回日本血液学会学術集会
• [Presentation] ATRA dependent interaction of MED1 with oncofusion protein PML-RARα initiates transcriptional activation (2019)
  • Author(s): Tomoya Fukuoka, Miki Matsuo, Hikaru Tsutsumi, Rino Kishida, Manami Tsuji, Mana Morikawa, Mizuha Anamoto, Naoya Kanada, Kyo Saiki, Robert G. Roeder, Natsumi Hasegawa, Mitsuhiro Ito
  • Organizer: 第42回日本分子生物学会年会
• [Presentation] Matrix Gla protein is a niche factor that supports myeloid leukemic cells without Glu γ-carboxylation. (2019)
  • Author(s): Mai Tsuruta, Kana Kuronuma, Leo Matsubara, Haruka Murata, Hikari Okamoto, Hao-Wei Han, Tomoya Fukuoka, Miki Matsuo, Shun Ito, Natsumi Hasegawa, Shigetaka Asano, Mitsuhiro Ito
  • Organizer: 第42回日本分子生物学会年会
• [Presentation] Translin modulates mesenchymal cell proliferation and differentiation in mice (2019)
  • Author(s): Kana Kuronuma, Yukiko Ikeuchi, Azusa Imanishi, Katsuko Sudo, Takako Fukunaga, Leo Matsubara, Aya Yokoi, Chie Goto, Tomoya Fukuoka, Miki Matsuo, Ruri Kono, Natsumi Hasegawa, Shigetaka Asano, Mitsuhiro Ito
  • Organizer: 第42回日本分子生物学会年会
• [Presentation] MGP interacts with BMP-4 and BMP-2 and supports normal and malignant hematopoietic stem/progenitor cells (2018)
  • Author(s): Aya Yokoi, Kana Kuronuma, Tomoya Fukuoka, Chie Goto, Miki Matsuo, Eri Adachi, Naoko Okada, Hikaru Tsutsumi, Mirano Kajitani, Natsumi Hasegawa, Shigetaka Asano, Mitsuhiro Ito
  • Organizer: 60th Annual Meeting of the American Society of Hematology
  • Int'l Joint Research
• [Presentation] Mediator transcriptional coregulatory complex interacts with GATA1 at its N-terminal activation domain (2018)
  • Author(s): Miki Matsuo, Tomoya Fukuoka, Hikaru Tsutsumi, Eri Adachi, Kie Hirano, Erika Haruna, Rino Kishida, Manami Tsuji, Tomomi Hisatsune, Natsumi Hasegawa, Mitsuhiro Ito
  • Organizer: 第41回日本分子生物学会年会
• [Presentation] CCL5は造血ニッチモデルにおいて白血病幹細胞の増殖を特異的に抑制する (2018)
  • Author(s): 後藤千恵、横井彩、黒沼加奈、岡田尚子、梶谷未来野、松原怜央、長谷川菜摘、浅野茂隆、伊藤光宏
  • Organizer: 第41回日本分子生物学会年会
• [Presentation] Role for MED1 in induction of group 2 innate lymphoid cells in visceral adipose tissue (2018)
  • Author(s): Eri Adachi, Kie Hirano, Chie Goto, Aya Yokoi, Kana Kuronuma, Erika Haruna, Rino Kishida, Robert G. Roeder, Natsumi Hasegawa, Tomoya Fukuoka, Mitsuhiro Ito
  • Organizer: 第80回日本血液学会学術集会
• [Presentation] MGP interacts with BMP-4 and supports normal and malignant hematopoietic stem/progenitor cells (2018)
  • Author(s): Kana Kuronuma, Aya Yokoi, Tomoya Fukuoka, Chie Goto, Eri Adachi, Miki Matsuo, Hikaru Tsutsumi, Naoko Okada, Mirano Kajitani, Shigetaka Asano, Mitsuhiro Ito
  • Organizer: 第80回日本血液学会学術集会
• [Presentation] Mediator transcriptional coregulatory complex interacts with GATA1 N-terminal activation domain (2018)
  • Author(s): Miki Matsuo, Tomoya Fukuoka, Hikaru Tsutsumi, Kie Hirano, Manami Tsuji, Tomomi Hisatsune, Robert G. Roeder, Natsumi Hasegawa, Mitsuhiro Ito
  • Organizer: 第80回日本血液学会学術集会
• [Presentation] 自家末梢血幹細胞移植における栄養状態と予後に関する後方視的解析 (2018)
  • Author(s): 水谷優、藥師神公和、市川大哉、坂井里奈、後藤秀彰、倉田啓史、西村明子、北尾章人、田淵聡子、瓜生恭章、垣内誠司、宮田吉晴、乾由美子、眞田幸尚、今村善宜、船越洋平、高橋路子、岡村篤夫、川本晋一郎、山本克也、伊藤光宏、松岡広、南博信
  • Organizer: 第40回日本造血移植学会総会、ロイトン札幌
• [Presentation] 非血縁者間骨髄移植前の病勢コントロールとしてGCD療法が有効であった肝脾原発T細胞リンパ腫の一例 (2018)
  • Author(s): 大國まりか、市川大哉、須藤洋崇、橋本朗子、田中康博、新里偉咲、長尾茂樹、坂井里奈、水谷優、北尾章人、倉田啓史、垣内誠司、宮田吉晴、乾由美子、斎藤泰之、藥師神公和、川本晋一郎、伊藤光宏、山本克也、松岡広、南博信
  • Organizer: 第40回日本造血移植学会総会、ロイトン札幌
• [Presentation] 全自動尿中有形成分分析装置 UF-5000 の性能評価 (2017)
  • Author(s): 牧 亜矢子、金山 敦子、井地 陽子、河野 江利子、池本 敏行、伊藤 光宏、岡田 仁克
  • Organizer: 第66回日本医学検査学会、幕張メッセ国際会議場
• [Presentation] 全自動尿中有形成分分析装置UF-5000による尿中細菌測定の有用性 (2017)
  • Author(s): 牧 亜矢子、金山 敦子、河野江利子、柴田 有理子、池本 敏行、伊藤 光宏、岡田 仁克
  • Organizer: 第64回日本臨床検査医学会学術集会,国立京都国際会館
• [Presentation] MGP is a novel niche factor for normal and malignant hematopoietic stem/precursor cells. (2017)
  • Author(s): Aya Yokoi, Chie Goto, Akio Maekawa, Leo Matsubara, Takako Fukunaga, Kana Kuronuma, Natsumi Hasegawa, Masamitsu Harada, Yoichi Nakao, Shigetaka Asano, Mitsuhiro Ito
  • Organizer: 第79 回日本血液学会学術集会、東京国際フォーラム
• [Presentation] Retrospective analysis of the ESHAP regimen for malignant lymphoma in Kobe University Hospital. (2017)
  • Author(s): Yoshiharu Miyata, Kimikazu Yakushijin, Hiroya Ichikawa, Rina Sakai, Hideaki Goto, Yu Mizutani, Keiji Kurata, Seiji Kakiuchi, Akihito Kitao, Shinichiro Kawamoto, Katsuya Yamamoto, Mitsuhiro Ito, Hiroshi Matsuoka, Hironobu Minami
  • Organizer: 第79 回日本血液学会学術集会、東京国際フォーラム
• [Presentation] MGP is a novel niche molecule that modulates normal and malignant hematopoietic stem/precursor cells. (2017)
  • Author(s): Aya Yokoi, Chie Goto, Kana Kuronuma, Akio Maekawa, Leo Matsubara, Takako Fukunaga, Natsumi Hasegawa, Masamitsu Harada, Shigetaka Asano, Mitsuhiro Ito
  • Organizer: 2017年度生命科学系学会合同年次大会（第40回日本分子生物学会年会・第90回日本生化学会大会）、神戸国際会議場
• [Presentation] 転写共役因子MED1の核内受容体結合能は低温環境での体温維持に必須である (2017)
  • Author(s): 平野希依、物延沙耶、安達枝里、長崎洋樹、福岡知也、峰松侑希、後藤千恵、横井彩、松尾美希、Robert G. Roeder、長谷川菜摘、伊藤光宏
  • Organizer: 2017年度生命科学系学会合同年次大会（第40回日本分子生物学会年会・第90回日本生化学会大会）、神戸国際会議場
• [Presentation] 転写共役因子MED1によるIL-33誘導性の2型自然リンパ球の動員調節 (2017)
  • Author(s): 安達枝里、長谷川菜摘、前川茜、物延沙耶、平野希依、後藤千恵、横井彩、黒沼加菜、宮田宗明、高井義美、Robert G. Roeder、伊藤光宏
  • Organizer: 2017年度生命科学系学会合同年次大会（第40回日本分子生物学会年会・第90回日本生化学会大会）、神戸国際会議場
• [Presentation] MED1の核内受容体結合能を廃絶した変異マウスにおける脂質代謝制御分子の発現 (2017)
  • Author(s): 物延沙耶、平野希依、安達枝里、峰松侑希、松尾美希、後和佳澄、服部美咲、黒沼加奈、Robert G. Roeder、長谷川菜摘、伊藤光宏
  • Organizer: 2017年度生命科学系学会合同年次大会（第40回日本分子生物学会年会・第90回日本生化学会大会）、神戸国際会議場
• [Presentation] GATA1のN端活性化ドメインを介する転写活性化におけるメディエーターの関与の可能性 (2017)
  • Author(s): 福岡知也、松尾美希、後和佳澄、森真洋、河合麻美、水田駿平、峰松侑希、服部美咲、Robert G. Roeder、長谷川菜摘、伊藤光宏
  • Organizer: 2017年度生命科学系学会合同年次大会（第40回日本分子生物学会年会・第90回日本生化学会大会）、神戸国際会議場
• [Book] 遺伝子発現制御機構 (2017)
  • Author(s): 田村 隆明、浦 聖惠他（分担執筆）
  • Total Pages: 264
  • Publisher: 東京化学同人
  • ISBN: 9784807909179
• [Remarks] 神戸大学保健学研究科 血液学研究室
  • URL: http://www2.kobe-u.ac.jp/~itomi/