Telomere repeat-containing RNA (TERRA), a possible molecular marker of leukemia

• Project/Area Number: 24501344
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Tumor diagnosis
• Research Institution: Tokyo Medical University
• Principal Investigator: OHYASHIKI Junko 東京医科大学, 医学部, 教授 (20191950)
• Co-Investigator(Renkei-kenkyūsha): UMEZU Tomohiro 東京医科大学, 医学部, 講師 (40385547)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: テロメアRNA / 5-アザシチジン / 骨髄異形成症候群 / 骨髄不全症候群 / DNAメチル化 / telomere RNA / 5-azacytidine

Outline of Final Research Achievements

Telomere repeat-containing RNAs (TERRAs), which are RNAs that originate from telomeric DNA transcription, can associate with the telomeric chromatin, where they are proposed to function as negative regulators of telomere length. In the current study, we established a RNA-FISH method for TERRA, and investigated the possible association between TERRA and 5-azacytidine (AZA), which is currently approved for the treatment of myeloid neoplasms. We found a constitutive up-regulation of TERRA in 2 AZA-resistant cell lines as well as bone marrow cells obtained from 3 AZA-resistant patients. These finding indicate that the RNA-FISH method for TERRA is useful not only to better understand molecular mechanism of AZA resistant but also to estimate AZA-resistant patients in clinical practice.

Research Products

• [Journal Article] Downregulated microRNA-148b in circulating PBMCs in chronic myeloid leukemia patients with undetectable minimal residual disease: a possible biomarker to discontinue imatinib safely. (2014)
  • Author(s): Ohyashiki JH, Ohtsuki K, Mizoguchi I, Yoshimoto T, Katagiri S, Umezu T, Ohyashiki K.
  • Journal Title: Drug Des Devel Ther. Volume: 8 Pages: 1151-1159
  • Peer Reviewed / Open Access
• [Journal Article] Constitutive activation of the ATM/BRCA1 pathway prevents DNA damage-induced apoptosis in 5-azacytidine-resistant cell lines. (2014)
  • Author(s): Imanishi S, Umezu T, Ohtsuki K, Kobayashi C, Ohyashiki K, Ohyashiki JH.
  • Journal Title: Biochem Pharmacol. Volume: 89 Issue: 3 Pages: 361-369
  • DOI: 10.1016/j.bcp.2014.03.008
  • Peer Reviewed
• [Journal Article] Exosomes derived from hypoxic leukemia cells enhance tube formation in endothelial cells. (2013)
  • Author(s): Tadokoro H, Umezu T, Ohyashiki K, Hirano T, and Ohyashiki JH.
  • Journal Title: J. Biol. Chem Volume: 288 Issue: 48 Pages: 34343-34351
  • DOI: 10.1074/jbc.m113.480822
  • Peer Reviewed
• [Journal Article] An association between ApoE 4/4 phenotype and telomere erosion in Alzheimer’s disease. (2012)
  • Author(s): Takata Y, Kikukawa M, Hanyu H, Koyama S, Shimizu S, Umahara T, Sakurai H, Iwamoto T, Ohyashiki K, Ohyashiki JH.
  • Journal Title: J Gerontol A Biol Sci Med Sci. Volume: 67 Pages: 330-335
  • Peer Reviewed
• [Journal Article] Telomere length shortening in patients with dementia with Lewy bodies. (2012)
  • Author(s): Kume K, Kikukawa M, Hanyu H, Takata Y, Umahara T, Sakurai H, Kanetaka H, Ohyashiki K, Ohyashiki JH,
  • Journal Title: Eur J Neurol. Volume: 19 Pages: 905-910
  • Peer Reviewed
• [Presentation] Telomere repeat-containing RNA (TERRA), a possible epigenetic biomarker of DNA damage phenotype in 5-azacytidine-resistant leukemia cells (2015)
  • Author(s): Kenko Azuma, Tomohiro Umezu, Satoshi Imanishi, Chiaki Kobayashi, Michiyo Asano, Seiichiro Katagiri, Daigo Akahane, Kazuma Ohyashiki, Junko H. Ohyashiki
  • Organizer: The 6th JSH International Symposium
  • Place of Presentation: 軽井沢
  • Year and Date: 2015-05-22
• [Presentation] テロメアRNA (TelRNA)を指標とした５―アザシチジン有効性の予測 (2014)
  • Author(s): 大屋敷純子、梅津知宏、今西 哲、東 剣虹、小林千晶、大屋敷一馬
  • Organizer: 第59回日本人類遺伝学会・第21回日本遺伝子診療学会合同大会
  • Place of Presentation: タワーホール船堀、船堀、東京
  • Year and Date: 2014-11-20 – 2014-11-22
• [Presentation] Towards comprehensive understanding of the mechanism underlying resistance to 5-azacytidine (2014)
  • Author(s): Imanishi S, Umezu T, Ohtsuki K, Kobayshi C, Ohyashiki K, Ohyashiki JH.
  • Organizer: 5th JSH International Symposium, 2014
  • Place of Presentation: アクトシティ浜松、浜松、静岡
  • Year and Date: 2014-05-24
• [Presentation] A possible association between 5-azacytidine sensitivity and epigenetic modulation of telomere in human leukemia cells. (2013)
  • Author(s): Ohyashiki JH, Umezu T, Kobayashi C, Imanishi S, Asano M, Ohyashiki K
  • Organizer: 12th International Symposium on MDS syndrome
  • Place of Presentation: Berlin, Germany
• [Presentation] Involvement of pyrimidine metabolism pathway in 5’-azacytidine resistance. (2013)
  • Author(s): Imanishi S, Umezu T, Kobayashi C, Ohyashiki K, Ohyashiki JH
  • Organizer: AACR Annual Meeting 2013
  • Place of Presentation: Washington DC, USA
• [Presentation] DNA methylated index of peripheral blood is a predictive marker for resistance to azacytidine in MDS patients. 12th International Symposium on MDS syndrome (2013)
  • Author(s): Asano M, Ohyashiki JH, Umezu T, Kobayashi C, Fujimoto H, Gotoh M, Alahane D, Kitahara T, Yoshizawa S, Ito Y, Ohyashiki K.
  • Organizer: 12th International Symposium on MDS syndrome
  • Place of Presentation: Berlin, Germany
• [Presentation] A possible role of DNA damage/repair in 5-azacytidine resistant leukemia cells. (2013)
  • Author(s): Imanishi S, Umezu T, Ohtsuki K, Kobayashi C, Ohyashiki K, Ohyashiki JH
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜
• [Presentation] DNA demethylation and up-regulation of telomere repeat-containing RNAs (TERRAs) in human leukemia cells. (2012)
  • Author(s): 大屋敷純子、梅津知宏、小林千晶、大屋敷一馬
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌