Establishment of predictive marker for epigenetic drugs in hematological malignancies

• Project/Area Number: 23590687
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Laboratory medicine
• Research Institution: Kitasato University
• Principal Investigator: TAKAHASHI Shinichiro 北里大学, 医療衛生学部, 教授 (40375069)
• Co-Investigator(Renkei-kenkyūsha): SATOH Takashi 北里大学, 医療衛生学部, 講師 (90407114)
• Project Period (FY): 2011-04-28 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2013: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2012: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2011: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: バイオマーカー / 分化 / PU.1 / メタロチオネイン / 白血病 / エピジェネティック

Outline of Final Research Achievements

First, we examined the effect of DNA methylation inhibitor on various PU.1 transgenic leukemia cell lines. As a result, we found a positive correlations for PU.1 expression and DNA methylation inhibitor effect, which induced differentiation and finally elimination of leukemia cells. Next, we assessed whether this effect is correlated with metallothionein (MT) expression, which we recently found an novel suppressive target gene of PU.1. To this aim, we generated MT over-expressed acute promyelocytic leukemia NB4 cell line (NB4MTOEcells) and examined the effect of all-trans retinoic acid (ATRA), which is a potent differentiation inducer for NB4 cells. We revealed that the effect of ATRA is inhibited in NB4MTOE cells. This is quite consistent with our prediction, because PU.1 is a suppressive regulator of MT. Collectively, these results suggest that expressions of PU.1 and MT may serve as useful biomarkers to predict the efficacy of epigenetic drugs which have differentiation effects.

Research Products

• [Journal Article] Positive and negative regulators of metallothionein gene (2015)
  • Author(s): Takahashi S
  • Journal Title: Molecular Medicine Reports Volume: in press Issue: 1 Pages: 795-799
  • DOI: 10.3892/mmr.2015.3459
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] The differentiation effect of low dose cytosine arabinoside is disturbed in PU.1-knockdown K562 cells (2014)
  • Author(s): Nakano H, Yanagita A, Takahashi S
  • Journal Title: Biomedical Reports Volume: 2 Issue: 4 Pages: 564-568
  • DOI: 10.3892/br.2014.265
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Allo-antigen stimulated CD8+ T cells Suppress NF-κB and Ets-1 DNA Binding Activity, and Inhibit Phosphorylated NF-κB p65 Nuclear Localization in CD4+ T cells (2014)
  • Author(s): Nagashima R, Kawakami F, Takahashi S, Obata F, Kubo M
  • Journal Title: Viral Immunology Volume: 27 Issue: 6 Pages: 305-315
  • DOI: 10.1089/vim.2013.0113
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] A PU.1 suppressive target gene, metallothionein 1G, inhibits retinoic acid-induced NB4 cell differentiation (2014)
  • Author(s): Hirako N, Nakano H, Takahashi S
  • Journal Title: PLOS ONE Volume: 9 Issue: 7 Pages: e103282-e103282
  • DOI: 10.1371/journal.pone.0103282
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The differentiation effect of low dose cytosine arabinoside is disturbed in PU.1-knockdown K562 cells (2014)
  • Author(s): Nakano H, Yanagita A and Takahashi S
  • Journal Title: Biomedical Reports Volume: in press
  • Peer Reviewed
• [Journal Article] Epigenetic regulation of the metallothionein-1A promoter by PU.1 during differentiation of THP-1 cells (2013)
  • Author(s): Suzuki S, Nakano H, Takahashi S
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 433 Issue: 3 Pages: 349-53
  • DOI: 10.1016/j.bbrc.2013.03.007
  • Peer Reviewed
• [Journal Article] Fcγ receptor IIB gene polymorphism in adult Japanese patients with primary immune thrombocytopenia. (2013)
  • Author(s): Satoh T1, Miyazaki K, Shimohira A, Amano N, Okazaki Y, Nishimoto T, Akahoshi T, Munekata S, Kanoh Y, Ikeda Y, Higashihara M, Takahashi S, Kuwana M.
  • Journal Title: Blood Volume: Sep 12;122 Issue: 11 Pages: 1991-2
  • DOI: 10.1182/blood-2013-05-501858
  • Peer Reviewed
• [Journal Article] Epigenetic aberrations in myeloid malignancies (Review). (2013)
  • Author(s): Takahashi S.
  • Journal Title: Int J Mol Med. Volume: Sep;32 Issue: 3 Pages: 532-8
  • DOI: 10.3892/ijmm.2013.1417
  • Peer Reviewed
• [Journal Article] Epigenetic aberrations in myeloid malignancies (2013)
  • Author(s): Takahashi S
  • Journal Title: International Journal of Molecular Medicine Volume: in press
  • Peer Reviewed
• [Journal Article] Gene Expression Profiling Identifies HOXB4 as a Direct Downstream Target of GATA-2 in Human CD34+ Hematopoietic Cells (2012)
  • Author(s): Fujiwara T, Yokoyama H, Okitsu Y, Kamata M, Fukuhara N, Onishi Y, Fujimaki S, Takahashi S, Ishizawa K, Bresnick E and Harigae H
  • Journal Title: PLoS ONE Volume: 7 Issue: 9 Pages: e40959-e40959
  • DOI: 10.1371/journal.pone.0040959
  • Peer Reviewed
• [Journal Article] Molecular functions of metallothionein and its role in hematological malignanceis (2012)
  • Author(s): Takahashi S
  • Journal Title: Journal of Hematology & Oncology Volume: 5 Issue: 1 Pages: 41-41
  • DOI: 10.1186/1756-8722-5-41
  • Peer Reviewed
• [Journal Article] Opposing Role, Depending on the Stage, of PU.1 during Erythroid Differentiation (2012)
  • Author(s): Takahashi S
  • Journal Title: Journal of Blood & Lymph Volume: 2 Issue: 02
  • DOI: 10.4172/2165-7831.1000e108
  • Peer Reviewed
• [Journal Article] The differentiating and apoptotic effects of 2-aza-5’-deoxycytidine are dependent on the PU.1 expression level in PU.1-transgenic K562 cells (2012)
  • Author(s): Aoyama S, Nakano H, Danbara M, Higashihara M, Harigae H, Takahashi S
  • Journal Title: Biochemical and Biophysical Research Communications Volume: in press Issue: 4 Pages: 775-781
  • DOI: 10.1016/j.bbrc.2012.03.071
  • Peer Reviewed
• [Journal Article] The expressions of PU.1 and signal regulatory protein alfa 1 are correlated in PU.1 transgenic K562 cells (2012)
  • Author(s): Iseki Y, Nakahara M, Kubo M, Obata F, Harigae H, Takahashi S
  • Journal Title: International Journal of Molecular Medicine Volume: 29(2) Pages: 319-23
  • DOI: 10.3892/ijmm.2011.827
  • Peer Reviewed
• [Journal Article] Activation of ERK and p38 by the addition of arsenic trioxide in Flt3-ITD cells (2011)
  • Author(s): Suzuki S, Inaba H, Satoh T, Okazaki T, Takahashi S
  • Journal Title: Open Journal of Blood Diseases Volume: 1(2) Issue: 02 Pages: 9-11
  • DOI: 10.4236/ojbd.2011.12003
  • Peer Reviewed
• [Journal Article] Current findings for recurring mutations in acute myeloid leukemia (2011)
  • Author(s): Takahashi S
  • Journal Title: Journal of Hematology and Oncology Volume: 4(36) Issue: 1 Pages: 1-11
  • DOI: 10.1186/1756-8722-4-36
  • Peer Reviewed
• [Journal Article] Downstream molecular pathways of FLT3 in the pathogenesis of acute myeloid leukemia: biology and therapeutic implications (2011)
  • Author(s): Takahashi S
  • Journal Title: Journal of Hematology and Oncology Volume: 4(13) Issue: 1 Pages: 1-10
  • DOI: 10.1186/1756-8722-4-13
  • Peer Reviewed
• [Journal Article] Effects of albumin bound fatty acids on the growth of the human T lymphoblastic cell line Jurkat (2011)
  • Author(s): Okazaki T, Iwasaki T, Fukuoka A, Suzuki M, Katagiri H, Okano T, Takahashi S
  • Journal Title: In Vitro Cellular & Developmental Biology-Animal Volume: 47(9) Issue: 9 Pages: 615-617
  • DOI: 10.1007/s11626-011-9454-z
  • Peer Reviewed
• [Presentation] Detection of Anti-Thrombopoietin antibodies in patients with immune thrombocytopenia (2014)
  • Author(s): Satoh T, Miyazaki T, Osawa E, Modegi N, Kita A, Kurihara S, Kawasaki Y, Shimada N, Nagane K, Higashihara M, Takahashi S
  • Organizer: American Society of Hematology Meeting
  • Place of Presentation: San Francisco Mascone Convention Center, San Francisco, USA
  • Year and Date: 2014-12-08
• [Presentation] 急性前骨髄性白血病(NB4)細胞におけるメタロチオネイン1G過剰発現の細胞分化・ストレス反応への影響 (2014)
  • Author(s): 平子奈緒美、中野博子、高橋伸一郎
  • Organizer: 日本分子生物学会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2014-11-26
• [Presentation] Analysis of anti-thrombopoietin antibody in patients with immune thrombocytopenia (2014)
  • Author(s): Satoh T, Miyazaki K, Shimada N, Nagane K, Kita A, Kurihara S, Kawasaki Y, Kodaira Y, Osawa E, Modegi N, Higashihara M, Takahashi S
  • Organizer: 日本血液学会
  • Place of Presentation: 大阪国際会議場（大阪府大阪市）
  • Year and Date: 2014-11-02
• [Presentation] メタロチオネイン1-Gの過剰発現は全トランス型レチノイン酸による急性前骨髄球性白血病細胞分化を阻害する (2014)
  • Author(s): 高橋伸一郎
  • Organizer: 日本検査血液学会
  • Place of Presentation: 仙台国際センター（宮城県仙台市）
  • Year and Date: 2014-07-20
• [Presentation] Detection of anti-thrombopoietin autoantibody among immune thrombocytopenic patients (2014)
  • Author(s): Miyazaki T, Satoh T, Osawa E, Modegi N, Kita A, Kurihara S, Kawasaki Y, Shimada N, Nagane K, Higashihara M, Takahashi S
  • Organizer: 19th Congress of European Hematology Association Meeting
  • Place of Presentation: Milano Congressi, Milan, Italy
  • Year and Date: 2014-06-13
• [Presentation] 免疫性血小板減少症におけるトロンボポエチンに対する自己抗体の解析 (2014)
  • Author(s): 佐藤隆司、宮崎浩二、大沢絵莉子、茂出木菜穂美、 喜多晃子、栗原紗恵子、川崎友里、小平祐衣、東原正明、高橋伸一郎
  • Organizer: 日本血栓止血学会学術集会
  • Place of Presentation: 大阪国際交流センター（大阪府大阪市）
  • Year and Date: 2014-05-31
• [Presentation] Acute myeloid leukemia biology: recurrent mutations, and analysis of PU.1 target genes (2014)
  • Author(s): Takahashi S
  • Organizer: Time on advances in haematological disorders, the “target therapy”
  • Place of Presentation: Ospedale Vincenzo Cervello, Palermo, Italy
  • Invited
• [Presentation] MT-1G disturbs ATRA induced differentiation of NB4 cells through the inhibition of p53 (2013)
  • Author(s): Hirako N, Nakano H and Takahashi S
  • Organizer: 日本血液学会
  • Place of Presentation: ロイトン札幌・さっぽろ芸文館・札幌市教育会館（札幌）
• [Presentation] 免疫性血小板減少症における抗トロンボポエチン抗体の解析 (2013)
  • Author(s): 佐藤隆司、宮崎浩二、大沢絵莉子、茂出木菜穂美、喜多晃子、栗原紗恵子、川崎友里、小平祐衣、東原正明、高橋伸一郎
  • Organizer: 日本臨床免疫学会総会
  • Place of Presentation: 海峡メッセ下関（下関）
• [Presentation] NB4細胞分化におけるPU.1標的遺伝子メタロチオネイン（MT）-1及びビメンチン（VIM）発現解析 (2011)
  • Author(s): 鈴木佐和美、高橋伸一郎他
  • Organizer: 第73回日本血液学会
  • Place of Presentation: 名古屋国際会議場（名古屋市）
• [Presentation] 5-aza-2'-deoxycytidineの細胞周期への影響はPU.1の発現量と関連する (2011)
  • Author(s): 青山紗由里、高橋伸一郎他
  • Organizer: 第73回日本血液学会
  • Place of Presentation: 名古屋国際会議場（名古屋市）
• [Presentation] Over-expression of Metallothionein-1 inhibits retinoic acid induced NB4 cell differentiation
  • Author(s): Takahashi S, Hirako N, Suzuki S and Nakano H
  • Organizer: 日本血液学会
  • Place of Presentation: 京都
• [Presentation] Analysis of Fcg receptor 2A, 2B and 3A polymorphisms in adults with immune thrombocytopenia
  • Author(s): Satoh T, Shimohira A, Amano N, Okazaki Y, Nishimoto T, Akahoshi T, Munekata S, Knoh Y, Okada J, Ikeda Y, Miyazaki K, Higashihara M, Kuwana M and Takahashi S
  • Organizer: 日本血液学会
  • Place of Presentation: 京都
• [Book] Myeloid Leukemia/ Basic Mechanisms of Leukemogenesis (Editor: Steffen Koschmieder and Utz Krug), Chapter 13 (2011)
  • Author(s): Takahashi S
  • Total Pages: 24
  • Publisher: Intech Open Access Publisher
• [Remarks] 北里大学医療衛生学部医療検査学科血液学研究室ホームページ
  • URL: http://www.kitasato-u.ac.jp/ahs/ml/ketsueki/
• [Remarks] 大学プレスセンター 北里大学が顆粒球系細胞分化を制御する遺伝子を新たに同定
  • URL: http://www.u-presscenter.jp/modules/bulletin/index.php?page=article&storyid=7318
• [Remarks] 北里大学医療衛生学部血液学ホームページ
  • URL: http://www.kitasato-u.ac.jp/ahs/ml/ketsueki/
• [Remarks] 北里大学医療衛生学部血液学ホームページ
  • URL: http://www.ahs.kitasato-u.ac.jp/~hematolo/index.html
• [Remarks]
  • URL: http://www.ahs.kitasato-u.ac.jp/~hematolo/takahashiaml.html