In vivo stem cell tracking of myeloproliferative disease and identification of novel molecular targets

• Project/Area Number: 26860721
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Hematology
• Research Institution: The University of Tokyo
• Principal Investigator: SATO TOMOHIKO 東京大学, 医学部附属病院, 研究員 (90553694)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 白血病幹細胞 / 白血病モデルマウス / 造血幹細胞 / 遺伝子変異 / 慢性骨髄単球性白血病 / 遺伝子異常 / 骨髄性白血病

Outline of Final Research Achievements

In CMML-developed Evi1-GFP;Kras-mutant mice, no GFP(Evi1)-positive leukemia cells were detected.
Even after 20-month observation, Evi1-GFP;ASXL-mutant knock-in mice looked healthy with no apparent signs of acute myeloid leukemia or myelodysplastic syndrome. ASXL-mutant knock-in BM cells showed a skewed differentiation to myeloid lineage. ASXL-mutant knock-in BM cells had 2.3-times higher hematopoietic colony formation capacity and higher replating capacity up to five times. These cells had a similar BM reconstituting capacity to wild type BM cells (eight-month observation). Retroviral CML induction to ASXL-mutant knock-in BM cells showed no acceleration of CML development, but recipients with IDH1-mutant transduced ASXL-mutant knock-in BM cells had leukemia development with 10-month duration while ASXL-wild counterparts showed no leukemia so far.

Research Products

• [Journal Article] Evi1 defines leukemia-initiating capacity and tyrosine kinase inhibitor resistance in chronic myeloid leukemia. (2014)
  • Author(s): Sato T, Goyama S, Kataoka K, Nasu R, Tsuruta-Kishino T, Kagoya Y, Nukina A, Kumagai K, Kubota N, Nakagawa M, Arai S, Yoshimi A, Honda H, Kadowaki T, Kurokawa M.
  • Journal Title: Oncogene Volume: 33 Issue: 42 Pages: 5028-5038
  • DOI: 10.1038/onc.2014.108
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Evi1 Defines Leukemia-initiating Capacity and Tyrosine Kinase Inhibitor Resistance in Chronic Myeloid Leukemia (2014)
  • Author(s): Tomohiko Sato, Susumu Goyama, Keisuke Kataoka, Ryo Nasu, Takako Tsuruta-Kishino, Yuki Kagoya, Arika Nukina, Katsuyoshi Kumagai, Naoto Kubota, Masahiro Nakagawa, Shunya Arai, Akihide Yoshimi, Hiroaki Honda, Takashi Kadowaki and Mineo Kurokawa
  • Organizer: AACR 2014
  • Place of Presentation: San Diego Convention Center
  • Year and Date: 2014-04-05 – 2014-04-09