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.

• Authors: D Inoue, J Kitaura, H Matsui, H-A Hou, W-C Chou, A Nagamachi, K C Kawabata, K Togami, R Nagase, S Horikawa, M Saika, J-B Micol, Y Hayashi, Y Harada, H Harada, T Inaba, H-F Tien, O Abdel-Wahab, T Kitamura
• Journal: Leukemia (Leukemia) Vol. 29 Issue 4 Pg. 847-57 (Apr 2015) ISSN: 1476-5551 [Electronic] England
• PMID: 25306901 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• ASXL1 protein, human
• Carrier Proteins
• Homeodomain Proteins
• Nuclear Proteins
• Repressor Proteins
• SETBP1 protein, human
• Transforming Growth Factor beta
• HoxA protein
• Proto-Oncogene Proteins c-akt
• Protein Phosphatase 2

Topics

• Adult
• Animals
• Apoptosis
• Carrier Proteins (genetics, metabolism)
• Cell Differentiation
• Cell Transformation, Neoplastic (genetics, metabolism, pathology)
• Gene Expression Regulation, Leukemic
• HEK293 Cells
• HL-60 Cells
• Homeodomain Proteins (genetics, metabolism)
• Humans
• Leukemia, Myeloid, Acute (genetics, metabolism, mortality, pathology)
• Mice
• Mice, Inbred C57BL
• Mutation
• Myelodysplastic Syndromes (genetics, metabolism, mortality, pathology)
• Nuclear Proteins (genetics, metabolism)
• Protein Phosphatase 2 (genetics, metabolism)
• Proteolysis
• Proto-Oncogene Proteins c-akt (genetics, metabolism)
• Repressor Proteins (genetics, metabolism)
• Signal Transduction
• Survival Analysis
• Transforming Growth Factor beta (genetics, metabolism)
• Ubiquitination