The role of SETBP1 mutation in leukemic transformation

• Project/Area Number: 26893051
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: Hematology
• Research Institution: The University of Tokyo
• Principal Investigator: Inoue Daichi 東京大学, 医科学研究所, 特任助教 (80735746)
• Project Period (FY): 2014-08-29 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 骨髄異形成症候群 / 急性骨髄性白血病 / エピジェネティクス / TGFβ / 形質転換

Outline of Final Research Achievements

Mutations in ASXL1 are frequent in patients with MDS and are associated with adverse survival. Here, we find that SETBP1-MT are enriched among ASXL1-mutated MDS patients and associated with increased incidence of leukemic transformation, as well as shorter survival, suggesting that SETBP1-MT play a critical role in leukemic transformation of MDS. Expression of SETBP1-MT inhibited protein PP2A activity, leading to Akt activation and enhanced expression of posterior Hoxa genes in ASXL1-mutant cells. Biologically, SETBP1-MT augmented ASXL1-MT-induced differentiation block, inhibited apoptosis and enhanced myeloid colony output. SETBP1-MT collaborated with ASXL1-MT in inducing acute myeloid leukemia in vivo. The combination of ASXL1-MT and SETBP1-MT repressed the tumor growth factor-β signaling pathway. These data reveal that SETBP1-MT are critical drivers of ASXL1-mutated MDS and identify several deregulated pathways as potential therapeutic targets in high-risk MDS.

Research Products

• [Journal Article] Truncation mutants of ASXL1 observed in myeloid malignancies are expressed at detectable protein levels. (2016)
  • Author(s): Inoue D, Matsumoto M, Nagase R, Saika M, Fujino T, Nakayama KI, Kitamura T.
  • Journal Title: Exp Hematol. Volume: 44 Issue: 3 Pages: 172-176
  • DOI: 10.1016/j.exphem.2015.11.011
  • Peer Reviewed
• [Journal Article] SETBP1 mutations drive leukemic transformation in ASXL1-mutated MDS. (2015)
  • Author(s): Inoue D, Kitaura J, Matsui H, Hou HA, Chou WC, Nagamachi A, Kawabata KC, Togami K, Nagase R, Horikawa S, Saika M, Micol JB, Hayashi Y, Harada Y, Harada H, Inaba T, Tien HF, Abdel-Wahab O, Kitamura T.
  • Journal Title: Leukemia Volume: 29(4) Issue: 4 Pages: 847-57
  • DOI: 10.1038/leu.2014.301
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Novel roles of ASXL1 in epigenetic regulation (2015)
  • Author(s): Daichi Inoue, Sayuri Horikawa, Hirotaka Matsui. Reina Nagase, Makoto Saika, Kimihito Kawabata, Susumu Goyama, Toshio Kitamura
  • Organizer: ISEH 44th Annual Scientific Meeting
  • Place of Presentation: 国立京都国際会館（京都府・京都市）
  • Year and Date: 2015-09-18
  • Int'l Joint Research
• [Presentation] SETBP1 Mutations Drive Leukemic Transformation in ASXL1-Mutated MDS (2014)
  • Author(s): Inoue D, Kitamura T
  • Organizer: The 56th American Society of Hematology annual meeting
  • Place of Presentation: 米国 サンフランシスコ
  • Year and Date: 2014-12-08
• [Presentation] SETBP1 Mutations Drive Leukemic Transformation in ASXL1-Mutated MDS (2014)
  • Author(s): Inoue D, Kitamura T
  • Organizer: 第76回日本血液学会総会
  • Place of Presentation: 大阪 国際会議場
  • Year and Date: 2014-10-31
• [Remarks] 東京大学医科学研究所北村研究室
  • URL: http://www.ims.u-tokyo.ac.jp/clinical_oncol/result.html