Inoue D.Kitaura J.Matsui H.HSIN-AN HOUWEN-CHIEN CHOUNagamachi A.Kawabata K.C.Togami K.Nagase R.Horikawa S.Saika M.Micol J.-B.Hayashi Y.Harada Y.Harada H.Inaba T.HWEI-FANG TIENAbdel-Wahab O.Kitamura T.2021-01-042021-01-0420150887-6924https://www.scopus.com/inward/record.uri?eid=2-s2.0-84927699006&doi=10.1038%2fleu.2014.301&partnerID=40&md5=2582f632a45b2a24799c8b408c1d9bd5https://scholars.lib.ntu.edu.tw/handle/123456789/537426Mutations in ASXL1 are frequent in patients with myelodysplastic syndrome (MDS) and are associated with adverse survival, yet the molecular pathogenesis of ASXL1 mutations (ASXL1-MT) is not fully understood. Recently, it has been found that deletion of Asxl1 or expression of C-terminal-truncating ASXL1-MTs inhibit myeloid differentiation and induce MDS-like disease in mice. Here, we find that SET-binding protein 1 (SETBP1) mutations (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. We identify that SETBP1-MT inhibit ubiquitination and subsequent degradation of SETBP1, resulting in increased expression. Expression of SETBP1-MT, in turn, inhibited protein phosphatase 2A 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 activated a stem cell signature and repressed the tumor growth factor-β signaling pathway, in contrast to the ASXL1-MT-induced MDS model. 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. ? 2015 Macmillan Publishers Limited.[SDGs]SDG3binding protein; cancer growth factor; phosphoprotein phosphatase 2A; protein kinase B; SET binding protein 1; tumor growth factor beta; unclassified drug; ASXL1 protein, human; carrier protein; homeodomain protein; HoxA protein; nuclear protein; phosphoprotein phosphatase 2; protein kinase B; repressor protein; SETBP1 protein, human; transforming growth factor beta; acute granulocytic leukemia; adult; animal cell; animal experiment; animal model; apoptosis; Article; ASXL1 gene; controlled study; differentiation; enzyme activity; female; gene; gene expression; gene mutation; Hoxa gene; human; human cell; in vivo study; major clinical study; mouse; myelodysplastic syndrome; nonhuman; priority journal; protein degradation; protein expression; SETBP1 gene; stem cell; survival; ubiquitination; acute myeloblastic leukemia; animal; C57BL mouse; cell differentiation; cell transformation; gene expression regulation; genetics; HEK293 cell line; HL 60 cell line; metabolism; mortality; mutation; myelodysplastic syndrome; pathology; signal transduction; survival analysis; Adult; Animals; Apoptosis; Carrier Proteins; Cell Differentiation; Cell Transformation, Neoplastic; Gene Expression Regulation, Leukemic; HEK293 Cells; HL-60 Cells; Homeodomain Proteins; Humans; Leukemia, Myeloid, Acute; Mice; Mice, Inbred C57BL; Mutation; Myelodysplastic Syndromes; Nuclear Proteins; Protein Phosphatase 2; Proteolysis; Proto-Oncogene Proteins c-akt; Repressor Proteins; Signal Transduction; Survival Analysis; Transforming Growth Factor beta; Ubiquitinationjournal article10.1038/leu.2014.301253069012-s2.0-84927699006