Mechanism of the maintenance of hematopoietic and leukemia stem cells by deubiquitinating enzyme USP10

• Project/Area Number: 15K09469
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Kanazawa Medical University (2016-2017); Niigata University (2015)
• Principal Investigator: HIGUCHI Masaya 金沢医科大学, 医学部, 教授 (50334678)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: USP10 / 造血肝細胞 / 脱ユビキチン化酵素 / アポトーシス / 造血幹細胞 / DNAダメージ応答 / 骨髄不全

Outline of Final Research Achievements

Ubiquitin specific peptidase 10 (USP10) is involved in cellular stress responses and we made USP10 knockout (KO) mice to analyze its in vivo functions. All USP10 KO mice died within 1 year after birth because of bone marrow failure with pancytopenia. Bone marrow failure in these USP10-KO mice was associated with remarkable reductions of hematopoieic stem cells (HCSs) in bone marrow and fetal liver. Such USP10-KO fetal liver started to exhibit enhanced apoptosis of HSCs at around E14.5. Transplantation of USP10 KO HSCs into irradiated WT mice failed to reconstitute multilineage hematopoiesis, whereas transplantation of USP10-competent bone marrow cells into USP10-KO mice did. These results suggest that USP10 is an essential deubiquitinase for hematopoiesis and functions by inhibiting apoptosis of HSCs.

Research Products

• [Journal Article] MAGI-1 expression is decreased in several types of human T-cell leukemia cell lines, including adult T-cell leukemia. (2018)
  • Author(s): Kozakai T, Takahashi M, Higuchi M, Hara T, Saito K, Tanaka Y, Masuko M, Takizawa J, Sone H, Fujii M
  • Journal Title: International Journal of Hematology Volume: 107(3) Issue: 3 Pages: 337-344
  • DOI: 10.1007/s12185-017-2359-1
  • Peer Reviewed / Open Access
• [Journal Article] Sox2-dependent inhibition of p21 is associated with poor prognosis of endometrial cancer. (2017)
  • Author(s): Yamawaki K, Ishiguro T, Mori Y, Yoshihara K, Suda K, Tamura R, Yamaguchi M, Sekine M, Kashima K, Higuchi M, Fujii M, Okamoto K, Enomoto T
  • Journal Title: Cancer Sci. Volume: 108 Issue: 4 Pages: 632-640
  • DOI: 10.1111/cas.13196
  • Peer Reviewed / Open Access
• [Journal Article] USP10 Is an Essential Deubiquitinase for Hematopoiesis and Inhibits Apoptosis of Long-Term Hematopoietic Stem Cells. (2016)
  • Author(s): Higuchi M, Kawamura H, Matsuki H, Hara T, Takahashi M, Saito S, Saito K, Jiang S, Naito M, Kiyonari H, Fujii M.
  • Journal Title: Stem Cell Reports Volume: ７ Issue: 6 Pages: 1116-1129
  • DOI: 10.1016/j.stemcr.2016.11.003
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] リン酸化 SIRT1 は過剰な複製開始を防止することで染色体安定性へ寄与する (2017)
  • Author(s): 宇谷公一、清水典明、樋口雅也
  • Organizer: 第７6回日本癌学会学術総会
• [Presentation] 脱ユビキチン化酵素USP10は造血幹細胞の維持に必須である (2016)
  • Author(s): 樋口雅也、大桑孝子、姫田敏樹、川村宏樹、藤井雅寛
  • Organizer: 第53回日本細菌学会中部支部会
  • Place of Presentation: 日本歯科大学新潟生命歯学部（新潟県新潟市）
  • Year and Date: 2016-10-28
• [Presentation] Ubiquitin specific protease 10 is essential for hematopoietic stem cell maintenance (2015)
  • Author(s): Masaya Higuchi, Hiroki Kawamura, Toshifumi Hara, Masahiko Takahashi, Masahiro Fujii
  • Organizer: The 77th annual meeting of the Japanese society of hematology
  • Place of Presentation: Hotel Nikko Kanazawa (石川県金沢市）
  • Year and Date: 2015-10-16