Department of Health Sciences, University of Milano-Bicocca, Monza, Italy.
Nat Genet. 2013 Jan;45(1):18-24. doi: 10.1038/ng.2495. Epub 2012 Dec 9.
Atypical chronic myeloid leukemia (aCML) shares clinical and laboratory features with CML, but it lacks the BCR-ABL1 fusion. We performed exome sequencing of eight aCMLs and identified somatic alterations of SETBP1 (encoding a p.Gly870Ser alteration) in two cases. Targeted resequencing of 70 aCMLs, 574 diverse hematological malignancies and 344 cancer cell lines identified SETBP1 mutations in 24 cases, including 17 of 70 aCMLs (24.3%; 95% confidence interval (CI) = 16-35%). Most mutations (92%) were located between codons 858 and 871 and were identical to changes seen in individuals with Schinzel-Giedion syndrome. Individuals with mutations had higher white blood cell counts (P = 0.008) and worse prognosis (P = 0.01). The p.Gly870Ser alteration abrogated a site for ubiquitination, and cells exogenously expressing this mutant exhibited higher amounts of SETBP1 and SET protein, lower PP2A activity and higher proliferation rates relative to those expressing the wild-type protein. In summary, mutated SETBP1 represents a newly discovered oncogene present in aCML and closely related diseases.
非典型慢性髓性白血病 (aCML) 在临床和实验室特征上与 CML 相似，但缺乏 BCR-ABL1 融合。我们对 8 例 aCML 进行了外显子组测序，在 2 例中发现 SETBP1 的体细胞改变（编码 p.Gly870Ser 改变）。对 70 例 aCML、574 种不同的血液恶性肿瘤和 344 种癌细胞系进行靶向重测序，发现 SETBP1 突变在 24 例中，包括 70 例 aCML 中的 17 例（24.3%；95%置信区间 (CI) = 16-35%）。大多数突变（92%）位于 858 至 871 密码子之间，与 Schinzel-Giedion 综合征个体所见的变化相同。有突变的个体白细胞计数更高（P = 0.008），预后更差（P = 0.01）。p.Gly870Ser 改变使泛素化位点失活，与表达野生型蛋白的细胞相比，外源性表达这种突变体的细胞中 SETBP1 和 SET 蛋白的含量更高，PP2A 活性更低，增殖速度更快。总之，突变的 SETBP1 代表一种新发现的癌基因，存在于 aCML 和密切相关的疾病中。
