TET2 gene abnormality and epigenetic dysregulation in hematologic malignancies

• Project/Area Number: 24390241
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: University of Tsukuba
• Principal Investigator: CHIBA Shigeru 筑波大学, 医学医療系, 教授 (60212049)
• Co-Investigator(Renkei-kenkyūsha): OGAWA Seishi 京都大学, 医学研究科, 教授 (60292900)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥17,940,000 (Direct Cost: ¥13,800,000、Indirect Cost: ¥4,140,000); Fiscal Year 2014: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2013: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2012: ¥7,150,000 (Direct Cost: ¥5,500,000、Indirect Cost: ¥1,650,000)
• Keywords: TET2 / T細胞リンパ腫 / エピゲノム / T細胞 / リンパ腫 / エピジェネティック制御 / エピジェネティック / 造血器腫瘍 / シトシン / メチル化

Outline of Final Research Achievements

Mutations in the TET2 gene, which encodes an enzyme converting methylcytosine to hydroxymethylcytosine in the genome, are frequently found in a wide variety of hematologic　malignancies. In this research, we demonstrated frequent novel RHOA gene mutations and the relationship between the mutations of TET2 and RHOA in angioimmunoblastic T-cell lymphoma. These findings were published in Nature Genetics in 2014. Furthermore, using model mice in which TET2 is knocked down, we demonstrated development of T-cell lymphoma and epigenetic dysregulation by the defect of TET2 function.

Research Products

• [Journal Article] Reduced TET2 function leads to T-cell lymphoma with follicular helper T-cell-like features in mice. (2014)
  • Author(s): Muto H, Sakata-Yanagimoto M, Nagae G, Shiozawa Y, Miyake Y, Yoshida K, Enami T, Kamada Y, Kato T, Uchida K, Nanmoku T, Obara N, Suzukawa K, Sanada M, Nakamura N, Aburatani H, Ogawa S, Chiba S
  • Journal Title: Blood Cancer J. Volume: 12 Issue: 12 Pages: e264-e264
  • DOI: 10.1038/bcj.2014.83
  • Peer Reviewed / Open Access
• [Journal Article] Detection of the G17V RHOA mutation in angioimmunoblastic T-cell lymphoma and related lymphomas using quantitative allele-specific PCR (2014)
  • Author(s): Nakamoto-Matsubara R, Sakata-Yanagimoto M, Enami T, Yoshida K, Yanagimoto S, Shiozawa Y, Nanmoku T, Satomi K, Muto H, Obara N, Kato T, Kurita N, Yokoyama Y, Izutsu K, Ota Y, Sanada M, Shimizu S, Komeno T, Sato Y, Ito T, Kitabayashi I, Takeuchi K, Nakamura N, Ogawa S, Chiba S.
  • Journal Title: PLoS ONE Volume: 9 Issue: 10 Pages: e109714-e109714
  • DOI: 10.1371/journal.pone.0109714
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Hes1 suppresses acute myeloid leukemia development through FLT3 repression (2014)
  • Author(s): Kato T, Sakata-Yanagimoto M, Nishikii H, Miyake Y, Yokayama Y, Asabe Y, Kamada Y, Ueno M, Obara N, Suzukawa K, Hasegawa Y, Kitabayashi I, Uchida K, Hirao A, Yagita H, Kageyama R, Chiba S
  • Journal Title: Leukemia Volume: 29 Issue: 3 Pages: 576-585
  • DOI: 10.1038/leu.2014.281
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Disease-Specific Mutations in Mature Lymphoid Neoplasms-Recent Advances (2014)
  • Author(s): Sakata-Yanagimoto M, Enami T, Yokoyama Y, Chiba S
  • Journal Title: Cancer Science Volume: 105 Issue: 6 Pages: 623-629
  • DOI: 10.1111/cas.12408
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Somatic RHOA mutation in angioimmunoblastic T cell lymphoma. (2014)
  • Author(s): Sakata-Yanagimoto M, Yoshida K
  • Journal Title: Nature Genet. Volume: 46 Issue: 2 Pages: 171-175
  • DOI: 10.1038/ng.2872
  • Peer Reviewed
• [Journal Article] Notch2 and Immune Function. (2012)
  • Author(s): Mamiko Sakata-Yanagimoto
  • Journal Title: Curr Top Microbiol Immunol Volume: 360 Pages: 151-161
  • Peer Reviewed
• [Journal Article] Identification of unbalanced genome copy number abnormalities in patients with multiple myeloma by single-nucleotide polymorphism genotyping microarray analysis. (2012)
  • Author(s): Yuhei Kamada
  • Journal Title: Int J Hematol Volume: 96 Issue: 4 Pages: 492-500
  • DOI: 10.1007/s12185-012-1171-1
  • Peer Reviewed
• [Presentation] Genetic analysis of T-cell lymphoma developed in TET2 knockdown mice (2014)
  • Author(s): 武藤秀治、千葉滋、他
  • Organizer: 第76回 日本血液学会学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2014-10-31 – 2014-11-02
• [Presentation] Mutations in epigenetic and metabolic regulators in peripheral T-cell lymphoma (2014)
  • Author(s): 坂田（柳元）麻実子、千葉滋
  • Organizer: 第76回 日本血液学会学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2014-10-31 – 2014-11-02
  • Invited
• [Presentation] Multistep tumorigenesis in peripheral T-cell lymphoma (2014)
  • Author(s): 坂田（柳元）麻実子、千葉滋
  • Organizer: 第73回 日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-25 – 2014-09-27
  • Invited
• [Presentation] TET2 binds and regulates O-linked N-acetylglucosamine transferase. (2013)
  • Author(s): Terukazu Enami, Mamiko-Sakata Yanagimoto, Yukitsugu Asabe, Yasuyuki Miyake, Satoshi Serada, Tetsuji Naka, Hideharu Muto, Hidekazu Nishikii, Yasuhisa Yokoyama, Naoshi Obara, Kazumi Suzukawa, Shigeru Chiba.
  • Organizer: 第75回日本血液学会学術集会
  • Place of Presentation: ロトイン札幌・ニトリ文化ホール・札幌市教育文化会館（札幌）
• [Presentation] Hypermethylation of Bcl6 Is a Potential Cause of Development of Lymphoma with Tfh Features in Tet2 Knockdown Mice (2013)
  • Author(s): Hideharu Muto, Mamiko Sakata-Yanagimoto, Yasuyuki Miyake, Genta Nagae, Terukazu Enami, Yuhei Kamada, Kazumi Suzukawa, Naoya Nakamura, Hiroyuki Aburatani, Seishi Ogawa, Shigeru Chiba.
  • Organizer: The American Society of Hematology 55th Annual Meeting and Exposition
  • Place of Presentation: Ernest N Morial Convention Center (New Orleans, LA, U.S.A.)
• [Presentation] 悪性リンパ腫細胞の起源とその進化 (2013)
  • Author(s): 千葉滋、坂田(柳元)麻実子
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（横浜）
  • Invited
• [Presentation] Transcription factor Hesl functions as a tumor suppressor in MLL-assosiated acute leukemias (2012)
  • Author(s): 加藤貴康
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌
• [Presentation] Reduced TET2 expression confers enhanced competitive repopulation capacity on HSCs (2012)
  • Author(s): 武藤秀治
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌
• [Presentation] DNA hydroxymethylation in hematologic malignancies (2012)
  • Author(s): 坂田(柳元) 麻実子
  • Organizer: 第74回日本血液学会学術集会
  • Place of Presentation: 京都(招待講演)
• [Remarks] 筑波大学血液内科
  • URL: http://www.ketsunai.com
• [Remarks] あるタイプの悪性リンパ腫に特異的な遺伝子変異の発見 ――早期診断法と新規治療薬の開発に期待――
  • URL: http://www.tsukuba.ac.jp/wp-content/uploads/p201401130300.pdf
• [Remarks]
  • URL: http://www.ketsunai.com
• [Patent(Industrial Property Rights)] T細胞リンパ腫の検出方法 (2013)
  • Inventor(s): 千葉滋、坂田(柳元)麻実子、小川誠司
  • Industrial Property Rights Holder: 筑波大学、東京大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2013-096582
  • Filing Date: 2013-05-01