{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Inoue D"],"funding":["Intramural NIH HHS","NCI NIH HHS"],"pagination":["847-57"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC4501574"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["29(4)"],"pubmed_abstract":["Mutations 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."],"journal":["Leukemia"],"pubmed_title":["SETBP1 mutations drive leukemic transformation in ASXL1-mutated MDS."],"pmcid":["PMC4501574"],"funding_grant_id":["K08 CA160647","1K08CA160647-01"],"pubmed_authors":["Kawabata KC","Harada Y","Hayashi Y","Kitaura J","Hou HA","Chou WC","Nagamachi A","Inaba T","Inoue D","Micol JB","Harada H","Nagase R","Kitamura T","Tien HF","Matsui H","Saika M","Horikawa S","Togami K","Abdel-Wahab O"],"additional_accession":[]},"is_claimable":false,"name":"SETBP1 mutations drive leukemic transformation in ASXL1-mutated MDS.","description":"Mutations 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.","dates":{"release":"2015-01-01T00:00:00Z","publication":"2015 Apr","modification":"2025-04-19T14:58:22.086Z","creation":"2019-03-27T01:55:06Z"},"accession":"S-EPMC4501574","cross_references":{"pubmed":["25306901"],"doi":["10.1038/leu.2014.301"]}}