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The pathogenesis of myeloproliferative neoplasms induced by TET2 mutation

Research Project

Project/Area Number 26461408
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Hematology
Research InstitutionUniversity of Miyazaki

Principal Investigator

Shimoda Kazuya  宮崎大学, 医学部, 教授 (90311844)

Project Period (FY) 2014-04-01 – 2017-03-31
Project Status Completed (Fiscal Year 2016)
Budget Amount *help
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Keywords骨髄増殖性腫瘍 / TET2 / JAK2
Outline of Final Research Achievements

Acquired mutations of JAK2 and TET2 are frequent in myeloproliferative neoplasms (MPNs). We examined the individual and cooperative effects of these mutations on MPN development. Recipients of JAK2V617F cells developed MPNs, and the addition of loss-of-TET2 worsened this JAK2V617F-induced disease. In a serial competitive transplantation assay, JAK2V617F cells resulted in decreased chimerism in the 2nd recipients, which did not develop MPNs. In contrast, cooperation between JAK2V617F and loss-of-TET2 developed and maintained MPNs in the 2nd recipients by compensating for impaired hematopoietic stem cell (HSC) functioning. Transcriptional profiling revealed that loss-of-TET2 affected the expression of many HSC signature genes. We conclude that loss-of-TET2 has two different roles in MPNs; one is as a disease accelerator, while the other is as a disease initiator and sustainer in combination with JAK2V617F.

Report

(4 results)
  • 2016 Annual Research Report   Final Research Report ( PDF )
  • 2015 Research-status Report
  • 2014 Research-status Report
  • Research Products

    (54 results)

All 2017 2016 2015 2014

All Journal Article (25 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 10 results,  Open Access: 7 results) Presentation (11 results) (of which Int'l Joint Research: 2 results) Book (17 results) Patent(Industrial Property Rights) (1 results)

  • [Journal Article] 骨髄疾患による貧血 骨髄線維症 疾患概念・病因・病態2017

    • Author(s)
      上運天綾子、下田和哉
    • Journal Title

      日本臨牀増刊号

      Volume: 75 Pages: 311-314

    • Related Report
      2016 Annual Research Report
  • [Journal Article] Effects of mogamulizumab in adult T-cell leukemia/lymphoma in clinical practice.2017

    • Author(s)
      Sekine M, Kubuki Y, Kameda T, Takeuchi M, Toyama T, Kawano N, Maeda K, Sato S, Ishizaki J, Kawano H, Kamiunten A, Akizuki K, Tahira Y, Shimoda H, Shide K, Hidaka T, Kitanaka A, Yamashita K, Matsuoka H, Shimoda K
    • Journal Title

      European journal of haematology.

      Volume: 98 Issue: 5 Pages: 501-507

    • DOI

      10.1111/ejh.12863

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Differences in Hematological and Clinical Features Between Essential Thrombocythemia Cases With JAK2- or CALR-Mutations.2017

    • Author(s)
      Kubuki Y, Shide K, Kameda T, Yamaji T, Sekine M, Kamiunten A, Akizuki K, Shimoda H, Tahira Y, Nakamura K, Abe H, Miike T, Iwakiri H, Tahara Y, Sueta M, Hashimoto K, Yamamoto S, Hasuike S, Hidaka T, Nagata K, Kitanaka A, Shimoda K
    • Journal Title

      Annals of laboratory medicine.

      Volume: 37 Issue: 2 Pages: 159-161

    • DOI

      10.3343/alm.2017.37.2.159

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] <i>TET2</i> mutation in diffuse large B-cell lymphoma2017

    • Author(s)
      Kubuki Y, Yamaji T, Hidaka T, Kameda T, Shide K, Sekine M, Kamiunten A, Akizuki K, Shimoda H, Tahira Y, Nakamura K, Abe H, Miike T, Iwakiri H, Tahara Y, Sueta M, Yamamoto S, Hasuike S, Nagata K, Kitanaka A, Shimoda K
    • Journal Title

      Journal of Clinical and Experimental Hematopathology

      Volume: 56 Issue: 3 Pages: 145-149

    • DOI

      10.3960/jslrt.56.145

    • NAID

      130005465221

    • ISSN
      1346-4280, 1880-9952
    • Related Report
      2016 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 遺伝子解析に基づくがん治療 骨髄増殖性腫瘍(MPN/CML)2016

    • Author(s)
      久冨木庸子、下田和哉
    • Journal Title

      がん分子標的治療Vol.14 No.1

      Volume: 14 Pages: 49-53

    • Related Report
      2016 Annual Research Report
  • [Journal Article] Ⅱ.本態性血小板血症の治療―アナグレリドの位置付け―2016

    • Author(s)
      北中明、下田和哉
    • Journal Title

      癌と化学療法

      Volume: 43 Pages: 535-538

    • Related Report
      2016 Annual Research Report
  • [Journal Article] 骨髄増殖性腫瘍に対するテロメラーゼ阻害薬imetelstatの効果2016

    • Author(s)
      秋月渓一、下田和哉
    • Journal Title

      血液フロンティア

      Volume: 26 Pages: 84-88

    • Related Report
      2016 Annual Research Report
  • [Journal Article] MPNの治療は,いつ開始すべきか?2016

    • Author(s)
      関根雅明、下田和哉
    • Journal Title

      血液内科

      Volume: 73 Pages: 57-62

    • Related Report
      2016 Annual Research Report
  • [Journal Article] Calreticulin mutant mice develop essential thrombocythemia that is ameliorated by the JAK inhibitor ruxolitinib2016

    • Author(s)
      Kotaro Shide, Takuro Kameda, Takumi Yamaji, Masaaki Sekine, Naoki Inada, Ayako Kamiunten, Keiichi Akizuki, Kenichi Nakamura, Akira Kitanaka, Arata Honda, Akira Sawaguchi, Hiroo Abe, Tadashi Miike, Hisayoshi Iwakiri, Yoshihiro Tahara, Mitsue Sueta, Satoru Hasuike, Shojiro Yamamoto, Kenji Nagata, and Kazuya Shimoda
    • Journal Title

      Leukemia

      Volume: 31 Issue: 5 Pages: 1136-1144

    • DOI

      10.1038/leu.2016.308

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] JAK2, MPL, CALR変異による骨髄増殖性腫瘍2016

    • Author(s)
      幣光太郎、下田和哉
    • Journal Title

      日本臨牀増刊号

      Volume: 74 Pages: 329-333

    • Related Report
      2016 Annual Research Report
  • [Journal Article] 骨髄増殖性腫瘍のWHO分類2016

    • Author(s)
      久冨木庸子、下田和哉
    • Journal Title

      日本臨牀増刊号

      Volume: 74 Pages: 381-385

    • Related Report
      2016 Annual Research Report
  • [Journal Article] 骨髄増殖性腫瘍 骨髄線維症の治療2016

    • Author(s)
      日高智徳、下田和哉
    • Journal Title

      日本臨牀増刊号

      Volume: 74 Pages: 191-195

    • Related Report
      2016 Annual Research Report
  • [Journal Article] 白血病における遺伝子ゲノム研究の動向 骨髄増殖性腫瘍2016

    • Author(s)
      亀田拓郎、下田和哉
    • Journal Title

      日本臨牀増刊号

      Volume: 74 Pages: 468-472

    • Related Report
      2016 Annual Research Report
  • [Journal Article] Splenic irradiation provides transient palliation for symptomatic splenomegaly associated with primary myelofibrosis: a report on 14 patients.2015

    • Author(s)
      Kitanaka A, Takenaka K, Shide K, Miyamoto T, Kondo T, Ozawa K, Kurokawa M, Akashi K, Shimoda K.
    • Journal Title

      Int J Hematol

      Volume: 103 Issue: 4 Pages: 423-428

    • DOI

      10.1007/s12185-016-1940-3

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] TET2 Mutation in Adult T-Cell Leukemia/Lymphoma2015

    • Author(s)
      Shimoda K, Shide K, Kameda T, Hidaka T, Kubuki Y, Kamiunten A, Sekine M, Akizuki K, Shimoda H, Yamaji T, Nakamura K, Abe H, Miike T, Iwakiri H, Tahara Y, Sueta M, Yamamoto S, Hasuike S, Nagata K, Kitanaka A
    • Journal Title

      Journal of Clinical and Experimental Hematopathology

      Volume: 55 Issue: 3 Pages: 145-149

    • DOI

      10.3960/jslrt.55.145

    • NAID

      130005119614

    • ISSN
      1346-4280, 1880-9952
    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Gene expression profiling of loss of TET2 and/or JAK2V617F mutant hematopoietic stem cells from mouse models of myeloproliferative neoplasms.2015

    • Author(s)
      Kameda T, Shide K, Yamaji T, Kamiunten A, Sekine M, Hidaka T, Kubuki Y, Sashida G, Aoyama K, Yoshimitsu M, Abe H, Miike T, Iwakiri H, Tahara Y, Yamamoto S, Hasuike S, Nagata K, Iwama A, Kitanaka A, Shimoda K
    • Journal Title

      Genom Data.

      Volume: 4 Pages: 102-108

    • DOI

      10.1016/j.gdata.2015.04.002

    • Related Report
      2015 Research-status Report 2014 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Functional analysis of TET2 using a knockdown mouse model2015

    • Author(s)
      幣光太郎、亀田拓郎、下田和哉
    • Journal Title

      Rinsho Ketsueki

      Volume: 56 Issue: 6 Pages: 657-665

    • DOI

      10.11406/rinketsu.56.657

    • NAID

      130005093100

    • ISSN
      0485-1439, 1882-0824
    • Related Report
      2015 Research-status Report
    • Peer Reviewed
  • [Journal Article] Genetic and epigenetic abnormalities in myeloproliferative neoplasms2015

    • Author(s)
      亀田拓郎、幣光太郎、下田和哉
    • Journal Title

      Rinsho Ketsueki

      Volume: 56 Issue: 6 Pages: 614-622

    • DOI

      10.11406/rinketsu.56.614

    • NAID

      130005093094

    • ISSN
      0485-1439, 1882-0824
    • Related Report
      2015 Research-status Report
    • Peer Reviewed
  • [Journal Article] 骨髄増殖性腫瘍におけるTET2欠損の役割2015

    • Author(s)
      亀田拓郎、幣光太郎、下田和哉
    • Journal Title

      血液内科

      Volume: 71 Pages: 411-416

    • NAID

      40020613861

    • Related Report
      2015 Research-status Report
  • [Journal Article] Resveratrol selectively induces apoptosis in malignant cells with the JAK2V617F mutation by inhibiting the JAK2 pathway.Molecular Nutrition & Food Research2015

    • Author(s)
      Trung LQ, Espinoza JL, An DT, Viet NH, Shimoda K, Nakao S
    • Journal Title

      Mol Nutr Food Res

      Volume: 59 Issue: 11 Pages: 2143-2154

    • DOI

      10.1002/mnfr.201500166

    • Related Report
      2015 Research-status Report
  • [Journal Article] Loss of TET2 has dual roles in murine myeloproliferative neoplasms: disease sustainer and disease accelerator.2015

    • Author(s)
      Kameda T, Shide K, Yamaji T, Kamiunten A, Sekine M, Taniguchi Y, Hidaka T, Kubuki Y, Shimoda H, Marutsuka K, Sashida G, Aoyama K, Yoshimitsu M, Harada T, Abe H, Miike T, Iwakiri H, Tahara Y, Sueta M, Yamamoto S, Hasuike S, Nagata K, Iwama A, Kitanaka A, Shimoda K.
    • Journal Title

      Blood

      Volume: 125 Issue: 2 Pages: 304-315

    • DOI

      10.1182/blood-2014-04-555508

    • NAID

      40020613861

    • Related Report
      2015 Research-status Report 2014 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] 骨髄増殖性腫瘍の分子機構と新規薬物療法2014

    • Author(s)
      北中明、幣光太郎、下田和哉
    • Journal Title

      臨床血液

      Volume: 54 Pages: 151-157

    • NAID

      10031196313

    • Related Report
      2014 Research-status Report
  • [Journal Article] 慢性骨髄増殖性腫瘍の癌幹細胞2014

    • Author(s)
      亀田拓郎,下田和哉
    • Journal Title

      医学のあゆみ

      Volume: 250 Pages: 15-21

    • Related Report
      2014 Research-status Report
  • [Journal Article] 骨髄線維症の病態と治療の進歩2014

    • Author(s)
      久冨木庸子,下田和哉
    • Journal Title

      最新医学

      Volume: 69 Pages: 90-96

    • Related Report
      2014 Research-status Report
  • [Journal Article] 骨髄の線維化とその治療2014

    • Author(s)
      下田和哉
    • Journal Title

      日本内科学会雑誌

      Volume: 103 Pages: 2193-2194

    • Related Report
      2014 Research-status Report
  • [Presentation] Mogamulizumab for adult T-cell leukemia/lymphoma in clinical practice.2016

    • Author(s)
      Masaaki Sekine, Yoko Kubuki, Takuro Kameda, Masaki Takeuchi, Takanori Toyama, Noriaki Kawano, Kouichi Maeda, Siichi Sato, Junzo Ishizaki, Hiroshi Kawano, Ayako Kamiunten, Keiichi Akizuki, Yuki Tahira, Haruko Shimoda, Kotaro Shide, Tomonori Hidaka, Akira Kitanaka, Kiyoshi Yamashita, Hitoshi Matsuoka, Kazuya Shimoda
    • Organizer
      58th ASH Annual Meeting & Exposition
    • Place of Presentation
      サンディエゴ(アメリカ合衆国)
    • Year and Date
      2016-12-03
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Physiological Expression of Calr Mutant Increases Cell Growth and Cytokine Independency in Human Cell Lines Expressing Mpl, and Develops Essential Thrombocythemia in Mice.2016

    • Author(s)
      Kotaro Shide, Takuro Kameda, Masaaki Sekine, Ayako Kamiunten, Keiichi Akizuki, Yuki Tahira, Tomonori Hidaka, Yoko Kubuki, Arata Honda, Akira Sawaguchi, Akira Kitanaka, Kazuya Shimoda
    • Organizer
      58th ASH Annual Meeting & Exposition
    • Place of Presentation
      サンディエゴ(アメリカ合衆国)
    • Year and Date
      2016-12-03
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] CALRdel52 mutation activates the JAK-STAT pathway in coordination with MPL, and causes ET in mice.2016

    • Author(s)
      Kotaro Shide, Takuro Kameda, Masaaki Sekine, Ayako Kamiunten, Keiichi Akizuki, Yuki Tahira, Haruko Shimoda, Tomonori Hidaka, Yoko Kubuki, Arata Honda, Akira Kitanaka, Kazuya Shimoda
    • Organizer
      第78回日本血液学会学術集会
    • Place of Presentation
      パシフィコ横浜(横浜市)
    • Year and Date
      2016-10-15
    • Related Report
      2016 Annual Research Report
  • [Presentation] TET2欠損はHBZトランスジェニックマウスの病態を増悪させる2016

    • Author(s)
      亀田拓郎、幣光太郎、関根雅明、山路卓巳、田平優貴、秋月渓一、上運天綾子、下田晴子、日髙智徳、久冨木庸子、北中明、下田和哉
    • Organizer
      第3回日本HTLV-1学会学術集会
    • Place of Presentation
      鹿児島県市町村自治会館(鹿児島市)
    • Year and Date
      2016-08-27
    • Related Report
      2016 Annual Research Report
  • [Presentation] 骨髄増殖性腫瘍の病態と治療2015

    • Author(s)
      下田和哉
    • Organizer
      第77回日本血液学会学術集会
    • Place of Presentation
      金沢市
    • Year and Date
      2015-10-16
    • Related Report
      2015 Research-status Report
  • [Presentation] Therapies targeting the MAPK pathway improve bone marrow (BM) fibrosis induced by JAK2V617F(JAK2VF)2015

    • Author(s)
      Kotaro Shide, Takuro Kameda, Ayako Kamiunten, Masaaki Sekine, Keiichi Akizuki, Haruko Shimoda, Tomonori Hidaka, Youko Kubuki, Akira Kitanaka, Kazuya Shimoda
    • Organizer
      第77回日本血液学会学術集会
    • Place of Presentation
      金沢市
    • Year and Date
      2015-10-16
    • Related Report
      2015 Research-status Report
  • [Presentation] Therapies Targeting the MAPK pathway improve bone marrow(BM) fibrosis induced by JAK2V617F2014

    • Author(s)
      Shide K,Kameda T, Shimoda H,Kamiunten A ,Sekine M, Hidaka T, Kubuki Y, Kitanaka A, Shimoda K
    • Organizer
      56th ASH Annual Meeting and Exposition
    • Place of Presentation
      San Fransisco CA, 米国
    • Year and Date
      2014-12-06 – 2014-12-09
    • Related Report
      2014 Research-status Report
  • [Presentation] Ezh2 loss accelerates JAK2V617F-driven primary myelofibrosis2014

    • Author(s)
      Sashida G, Tomioka T, Wang C, Shide K, Shimoda K, Iwama A
    • Organizer
      第76回日本血液学会学術集会
    • Place of Presentation
      大阪市
    • Year and Date
      2014-10-31 – 2014-11-02
    • Related Report
      2014 Research-status Report
  • [Presentation] Loss-of-TET2 induces clonal expansion of JAK2V617F mutant stem/progenitor cell and initiates MPNs2014

    • Author(s)
      Kamada T,Shide K, Akizuki K, Sekine M, Kamiunten A, Shimoda H, Hidaka T, Kubuki Y, Kitanaka A, Marutsuka K, Shimoda K
    • Organizer
      第76回日本血液学会学術集会
    • Place of Presentation
      大阪市
    • Year and Date
      2014-10-31 – 2014-11-02
    • Related Report
      2014 Research-status Report
  • [Presentation] MDS with extramedullary erythroid hypeplasia induced by loss of Tet2 in mice2014

    • Author(s)
      Muto T,Sashida G, Hasegawa N, Nakaseko C, Yokote K, Shimoda K, Iwama A
    • Organizer
      第76回日本血液学会学術集会
    • Place of Presentation
      大阪市
    • Year and Date
      2014-10-31 – 2014-11-02
    • Related Report
      2014 Research-status Report
  • [Presentation] Genetic and epigenetic abnormalities in myeloproliferative neoplasmas2014

    • Author(s)
      Shimoda K
    • Organizer
      第76回日本血液学会学術集会
    • Place of Presentation
      大阪市
    • Year and Date
      2014-10-31 – 2014-11-02
    • Related Report
      2014 Research-status Report
  • [Book] 貧血学―最新の診断・治療動向―2017

    • Author(s)
      上運天綾子、下田和哉
    • Total Pages
      644
    • Publisher
      日本臨牀社
    • Related Report
      2016 Annual Research Report
  • [Book] 血液疾患最新の治療2017-20192017

    • Author(s)
      日髙智徳、下田和哉
    • Total Pages
      370
    • Publisher
      南江堂
    • Related Report
      2016 Annual Research Report
  • [Book] 診断と治療のABC113 慢性骨髄背白血病 骨髄増殖性腫瘍2016

    • Author(s)
      亀田拓郎、下田和哉
    • Total Pages
      223
    • Publisher
      株式会社最新医学社
    • Related Report
      2016 Annual Research Report
  • [Book] 骨髄線維症(MF)~分子病態の解明から新規薬物治療薬の開発まで~2016

    • Author(s)
      幣光太郎、下田和哉
    • Total Pages
      187
    • Publisher
      株式会社医薬ジャーナル
    • Related Report
      2016 Annual Research Report
  • [Book] Ph陰性骨髄増殖性腫瘍~分子病態と治療の最前線~2016

    • Author(s)
      下田和哉
    • Total Pages
      123
    • Publisher
      株式会社医薬ジャーナル
    • Related Report
      2016 Annual Research Report
  • [Book] Ⅲ.白血病 E.骨髄増殖性腫瘍(MPN) 骨髄線維症の治療EBM 血液疾患の治療2016

    • Author(s)
      久冨木庸子、下田和哉
    • Total Pages
      541
    • Publisher
      株式会社中外医学社
    • Related Report
      2016 Annual Research Report
  • [Book] 白血病学(下)-最新の基礎,臨床研究-2016

    • Author(s)
      日高智徳、下田和哉
    • Total Pages
      582
    • Publisher
      日本臨牀社
    • Related Report
      2016 Annual Research Report
  • [Book] 白血病学(下)-最新の基礎,臨床研究-2016

    • Author(s)
      亀田拓郎、下田和哉
    • Total Pages
      582
    • Publisher
      日本臨牀社
    • Related Report
      2016 Annual Research Report
  • [Book] Hematology AGORA (血液の広場) 2015年春号2015

    • Author(s)
      北中明、下田和哉
    • Publisher
      株式会社 毘沙門堂
    • Related Report
      2015 Research-status Report
  • [Book] 血液専門医テキスト(改訂第2版)2015

    • Author(s)
      下田和哉
    • Total Pages
      576
    • Publisher
      株式会社 南江堂
    • Related Report
      2015 Research-status Report
  • [Book] 新臨床腫瘍学(改訂第4版) -がん薬物療法専門医のために-2015

    • Author(s)
      下田和哉
    • Publisher
      株式会社 南江堂
    • Related Report
      2015 Research-status Report
  • [Book] Principles and Practice 血液・造血器・リンパ系 医学生・レジデントのための必修エッセンス2015

    • Author(s)
      日高智徳、下田和哉
    • Total Pages
      383
    • Publisher
      株式会社 文光堂
    • Related Report
      2015 Research-status Report
  • [Book] 診療の手引きと臨床データ集 血液疾患診療ハンドブック 改訂3版2015

    • Author(s)
      幣光太郎、下田和哉
    • Total Pages
      591
    • Publisher
      医薬ジャーナル社
    • Related Report
      2015 Research-status Report
  • [Book] 難病事典2015

    • Author(s)
      北中明、下田和哉
    • Total Pages
      511
    • Publisher
      株式会社学研メディカル秀潤社
    • Related Report
      2015 Research-status Report
  • [Book] 今日の治療指針2016年版 私はこう治療している2015

    • Author(s)
      下田和哉
    • Publisher
      株式会社 医学書院
    • Related Report
      2015 Research-status Report
  • [Book] 血液疾患最新の治療2014-20162014

    • Author(s)
      上運天綾子,下田和哉
    • Total Pages
      373
    • Publisher
      南江堂
    • Related Report
      2014 Research-status Report
  • [Book] EBM血液疾患の治療 2015-20162014

    • Author(s)
      関根雅明,下田和哉
    • Total Pages
      555
    • Publisher
      中外医学社
    • Related Report
      2014 Research-status Report
  • [Patent(Industrial Property Rights)] 骨髄線維化の抑制剤2015

    • Inventor(s)
      幣光太郎、下田和哉
    • Industrial Property Rights Holder
      宮崎大学
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2015-016390
    • Filing Date
      2015-01-30
    • Related Report
      2014 Research-status Report

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Published: 2014-04-04   Modified: 2018-03-22  

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