Analysis of carcinogenesis based on TCR rearrangement system

• Project/Area Number: 25461580
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Takagi Masatoshi 東京医科歯科大学, 医歯(薬)学総合研究科, 准教授 (10406267)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2015: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2014: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000); Fiscal Year 2013: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: DNA損傷応答 / T細胞受容体 / ＤＮＡ損傷応答機構 / 毛細血管拡張性運動失調症 / 染色体転座 / ATM / VDJ

Outline of Final Research Achievements

The ATM deficient mouse exhibits fewer CD4 and CD8 single positive T-cells due to a failure to develop from the CD4+CD8+ double positive phase to the SP phase. Although the occurrence of chromosome 14 translocations involving TCR alpha gene in ATM-deficient lymphomas suggest that these are early events in T-cell development, an thorough analysis focusing on early T-cell development has never been performed. We demonstrate that ATM deficient T cell are perturbed in passing through the beta or gamma/delta selection checkpoint, leading in part to the developmental failure of T-cells. Detailed karyotype analysis employing in vitro thymocyte development system revealed that RAG mediated TCR alpha/delta locus breaks occur and are left unrepaired during the troublesome beta or gamma/delta selection checkpoints. By getting through these selection checkpoints some of the clones with random or non-random chromosomal translocations involving TC Ralpha/delta locus are selected and accumulate.

Research Products

• [Journal Article] DNA損傷応答異常症(Ataxia Telangiectasiaを含めて） (2015)
  • Author(s): 高木正稔
  • Journal Title: 小児内科 Volume: 47 Pages: 691-696
• [Journal Article] ATM(ataxia telangiectasia mutated) (2015)
  • Author(s): 高木正稔
  • Journal Title: 日本臨床 Volume: 73 Pages: 263-269
• [Journal Article] Dysregulation of the DNA Damage Response and KMT2A Rearrangement in Fetal Liver Hematopoietic Cells (2015)
  • Author(s): Nanya, M. Sato, M. Tanimoto, K. Tozuka, M. Mizutani, S. Takagi, M.
  • Journal Title: PLoS One Volume: 10 Issue: 12 Pages: e0144540-e0144540
  • DOI: 10.1371/journal.pone.0144540
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] ATM and SIRT6/SNF2H mediate transient H2AX stabilization when DSBs form by blocking HUWE1 to allow efficient γH2AX foci formation. (2015)
  • Author(s): Atsumi, Y., Minakawa, Y., Ono, M., Dobashi, S., Snohe, K., Shinohara, A., Takeda, S., Takagi, M., Takamatsu, N., Nakagama, H., Teraoka, H., and K.-I. Yoshioka
  • Journal Title: Cell Reports Volume: 13 Issue: 12 Pages: 2728-2740
  • DOI: 10.1016/j.celrep.2015.11.054
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Hematopoietic myeloid cell differentiation diminishes nucleotide excision repair (2014)
  • Author(s): Aoki, Y. Sato, A. Mizutani, S. Takagi, M.
  • Journal Title: Int J Hematol Volume: 100 Issue: 3 Pages: 260-5
  • DOI: 10.1007/s12185-014-1625-8
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] ATMによる腫瘍化制御 (2014)
  • Author(s): 高木正稔
  • Organizer: 日本放射線影響学会第57回大会
  • Place of Presentation: かごしま県民交流センター（鹿児島・鹿児島）
  • Year and Date: 2014-10-01 – 2014-10-03
• [Presentation] 毛細血管拡張性運動失調症-原発性免疫不全症から血液悪性腫瘍発症機構に迫る- (2013)
  • Author(s): 高木正稔
  • Organizer: 第75回日本血液学会学術集会
  • Place of Presentation: 札幌市、北海道