SETBP1 mutations drive leukemic transformation in ASXL1-mutated MDS

• Published in: Leukemia Vol. 29; no. 4; pp. 847 - 857
• Main 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.04.2015; Nature Publishing Group
• Subjects: 13/95; 45/23; 45/91; 631/67/1990/283/1897; 64/60; 82/1; 96/31; Acute myeloid leukemia; Adult; AKT protein; Animals; Apoptosis; Binding proteins; Cancer Research; Care and treatment; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cell Differentiation; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Cell Transformation, Neoplastic - pathology; Clonal deletion; Critical Care Medicine; Deregulation; Development and progression; Differentiation; Gene expression; Gene Expression Regulation, Leukemic; Gene mutations; Genetic aspects; Genetic transformation; Growth factors; Health aspects; HEK293 Cells; Hematology; HL-60 Cells; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Humans; Intensive; Internal Medicine; Leukemia; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - metabolism; Leukemia, Myeloid, Acute - mortality; Leukemia, Myeloid, Acute - pathology; Medicine; Medicine & Public Health; Mice; Mice, Inbred C57BL; Mutants; Mutation; Myelodysplastic syndrome; Myelodysplastic syndromes; Myelodysplastic Syndromes - genetics; Myelodysplastic Syndromes - metabolism; Myelodysplastic Syndromes - mortality; Myelodysplastic Syndromes - pathology; Myeloid leukemia; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Oncology; original-article; Pathogenesis; Phosphoprotein phosphatase; Protein phosphatase; Protein Phosphatase 2 - genetics; Protein Phosphatase 2 - metabolism; Proteins; Proteolysis; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Repressor Proteins - genetics; Repressor Proteins - metabolism; Risk factors; Signal Transduction; Stem cells; Survival; Survival Analysis; Therapeutic applications; Transformations; Transforming Growth Factor beta - genetics; Transforming Growth Factor beta - metabolism; Ubiquitin; Ubiquitination; Japan
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2014.301

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 ( S ETBP1 ) 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.