Analysis of the mechanisms of POEMS syndrome with immortalized megakaryocyte progenitor cell lines

• Project/Area Number: 17K09901
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Chiba University
• Principal Investigator: Takeuchi Masahiro 千葉大学, 医学部附属病院, 講師 (50466702)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 巨核球の機能解析 / POEMS症候群 / アナグレリド / iPS細胞由来巨核球細胞 / Anagrelide / 巨核球 / 免疫グロブリン / 血液内科学

Outline of Final Research Achievements

Although anagrelide is a widely used therapeutic agent for patients with essential thrombocythemia, the exact mechanism of action is unclear. Immortalized megakaryocyte progenitor cell lines (imMKCLs) were established from human induced pluripotent stem (iPS) cells. Both undifferentiated and differentiated imMKCLs were treated with several different concentrations of anagrelide and followed by mRNA sequencing and some assaying procedures. We successfully reproduced the platelets-lowering effect of anagrelide by using imMKCLs from human iPS cells which could generate functional platelets in vitro. We also demonstrated that anagrelide inhibits the proliferation in undifferentiated imMKCLs through specifically suppressing the megakaryogenesis and platelet-formation related genes, and the maturation in differentiated imMKCLs through the altering of cell cycle related genes.

Academic Significance and Societal Importance of the Research Achievements

iPS細胞由来巨核球細胞を用いて、作用機序の明らかでなかったアナグレリドの作用機序の一端を明らかにすることが出来た。これは将来、本態性血小板血症の治療薬の開発につながっていく可能性がある。また、本研究により、これまで単離が困難で研究が進みにくかった巨核球に関する研究を行う際にiPS細胞由来巨核球細胞を用いることで、より詳細な解析が行えることを明らかにすることが出来た。今後、巨核球が病態に関与していることが想定されているPOEMS症候群を始めとする疾患の研究に寄与することが出来るものと考えられる。

Research Products

• [Journal Article] Suppressive effects of anagrelide on cell cycle progression and the maturation of megakaryocyte progenitor cell lines in human induced pluripotent stem cells. (2019)
  • Author(s): Takaishi K, Takeuchi M, Tsukamoto S, Takayama N, Oshima M, Kimura K, Isshiki Y, Kayamori K, Hino Y, Oshima-Hasegawa N, Mitsukawa S, Takeda Y, Mimura N, Ohwada C, Iseki T, Nakamura S, Eto K, Iwama A, Yokote K, Nakaseko C, Sakaida E.
  • Journal Title: Haematologica. Volume: Sep 5 Issue: 5 Pages: 00-00
  • DOI: 10.3324/haematol.2018.214841
  • Peer Reviewed / Open Access
• [Presentation] Anagrelide Inhibits Proliferation and Platelet Generation in Immortalized Megakaryocyte Progenitor Cell Lines Established from Human Induced Pluripotent Stem Cells (2018)
  • Author(s): Koji Takaishi, Masahiro Takeuchi, Shokichi Tsukamoto, Naoya Takayama, Motohiko Oshima, Yusuke Isshiki, Kensuke Kayamori, Naoya Mimura, Chikako Ohwada, Tohru Iseki, Sou Nakamura, Koji Eto, Atsushi Iwama, Koutaro Yokote, Chiaki Nakaseko and Emiko Sakaida
  • Organizer: 2018 American Society of Hematology Annual Meeting