SETBP1 mutations drive leukemic transformation in ASXL1-mutated MDS.
SETBP1 mutations drive leukemic transformation in ASXL1-mutated MDS.
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DOI：
10.1038/leu.2014.301
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发表时间：
2015-04
期刊：
影响因子：
11.4
通讯作者：
Kitamura T
中科院分区：
文献类型：
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作者：
Inoue D;Kitaura J;Matsui H;Hou HA;Chou WC;Nagamachi A;Kawabata KC;Togami K;Nagase R;Horikawa S;Saika M;Micol JB;Hayashi Y;Harada Y;Harada H;Inaba T;Tien HF;Abdel-Wahab O;Kitamura T
ASXL 1突变在骨髓增生异常综合征（MDS）患者中很常见，并与不良生存率相关，但ASXL 1突变的分子发病机制尚未完全了解。最近，已经发现Asxl 1的缺失或C-末端截短ASXL 1突变（ASXL 1-MT）的表达抑制小鼠的骨髓分化并诱导MDS样疾病。在此，我们发现SETBP 1突变（SETBP 1-MT）在ASXL 1突变的MDS患者中富集，并与白血病转化的发生率增加以及生存期缩短相关，表明SETBP 1-MT在MDS的白血病转化中起关键作用。我们确定，SETBP 1-MT抑制泛素化和随后的降解SETBP 1，导致表达增加。SETBP 1-MT的表达反过来又抑制Pp 2a活性，导致Akt激活并增强ASXL 1突变细胞中后部Hoxa基因的表达。在生物学上，SETBP 1-MT增强了ASXL 1-MT诱导的分化阻滞，抑制了细胞凋亡，并增强了髓系集落输出。SETBP 1-MT与ASXL 1-MT在体内协同诱导AML。与ASXL 1-MT诱导的MDS模型相反，ASXL 1-MT和SETBP 1-MT的组合激活了干细胞特征并抑制了TGF-β信号通路。这些数据表明，SETBP 1-MT是ASXL 1突变型MDS的关键驱动因素，并确定了几种失调途径作为高危MDS的潜在治疗靶点。
Mutations in ASXL1 are frequent in patients with myelodysplastic syndrome (MDS) and associated with adverse survival yet the molecular pathogenesis of ASXL1 mutations are not fully understood. Recently it has been found that deletion of Asxl1 or expression of C-terminal-truncating ASXL1 mutations (ASXL1-MT) inhibit myeloid differentiation and induce MDS-like disease in mice. Here, we find that SETBP1 mutations (SETBP1-MT) are enriched among patients with ASXL1-mutated MDS patients and associated with increased incidence of leukemic transformation as well as shorter survival, suggesting 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 Pp2a 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 AML in vivo. The combination of ASXL1-MT and SETBP1-MT activated a stem cell signature and repressed the TGF-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.