SETBP1 mutations drive leukemic transformation in ASXL1-mutated MDS Journal Article
| Authors: | Inoue, D.; Kitaura, J.; Matsui, H.; Hou, H. A.; Chou, W. C.; Nagamachi, A.; Kawabata, K. C.; Togami, K.; Nagase, R.; Horikawa, S.; Saika, M.; Micol, J. B.; Hayashi, Y.; Harada, Y.; Harada, H.; Inaba, T.; Tien, H. F.; Abdel-Wahab, O.; Kitamura, T. |
| Article Title: | SETBP1 mutations drive leukemic transformation in ASXL1-mutated MDS |
| 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. © 2015 Macmillan Publishers Limited. |
| Keywords: | survival; protein kinase b; adult; controlled study; protein expression; unclassified drug; acute granulocytic leukemia; gene mutation; human cell; major clinical study; nonhuman; animal cell; mouse; gene; apoptosis; gene expression; protein degradation; animal experiment; animal model; in vivo study; enzyme activity; stem cell; myelodysplastic syndrome; ubiquitination; binding protein; differentiation; asxl1 gene; cancer growth factor; phosphoprotein phosphatase 2a; hoxa gene; human; female; priority journal; article; set binding protein 1; tumor growth factor beta; setbp1 gene |
| Journal Title: | Leukemia |
| Volume: | 29 |
| Issue: | 4 |
| ISSN: | 0887-6924 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2015-04-01 |
| Start Page: | 847 |
| End Page: | 857 |
| Language: | English |
| DOI: | 10.1038/leu.2014.301 |
| PROVIDER: | scopus |
| PUBMED: | 25306901 |
| PMCID: | PMC4501574 |
| DOI/URL: | |
| Notes: | Export Date: 4 May 2015 -- Source: Scopus |
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