The role of SETBP1 mutation in leukemic transformation

2015 Fiscal Year Final Research Report

• 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
• 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

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.

Free Research Field

血液内科学