Department of Pediatrics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
Department of Pediatrics, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima, Japan.
Nat Genet. 2017 Aug;49(8):1274-1281. doi: 10.1038/ng.3900. Epub 2017 Jul 3.
The outcome of treatment-refractory and/or relapsed pediatric T cell acute lymphoblastic leukemia (T-ALL) is extremely poor, and the genetic basis for this is not well understood. Here we report comprehensive profiling of 121 cases of pediatric T-ALL using transcriptome and/or targeted capture sequencing, through which we identified new recurrent gene fusions involving SPI1 (STMN1-SPI1 and TCF7-SPI1). Cases positive for fusions involving SPI1 (encoding PU.1), accounting for 3.9% (7/181) of the examined pediatric T-ALL cases, showed a double-negative (DN; CD4CD8) or CD8 single-positive (SP) phenotype and had uniformly poor overall survival. These cases represent a subset of pediatric T-ALL distinguishable from the known T-ALL subsets in terms of expression of genes involved in T cell precommitment, establishment of T cell identity, and post-β-selection maturation and with respect to mutational profile. PU.1 fusion proteins retained transcriptional activity and, when constitutively expressed in mouse stem/progenitor cells, induced cell proliferation and resulted in a maturation block. Our findings highlight a unique role of SPI1 fusions in high-risk pediatric T-ALL.
治疗抵抗和/或复发的儿科 T 细胞急性淋巴细胞白血病（T-ALL）的治疗效果极差，其遗传基础尚不清楚。在这里，我们使用转录组和/或靶向捕获测序对 121 例儿科 T-ALL 进行了全面分析，通过这些分析，我们鉴定了涉及 SPI1（STMN1-SPI1 和 TCF7-SPI1）的新的复发性基因融合。阳性融合涉及 SPI1（编码 PU.1）的病例占所检查的儿科 T-ALL 病例的 3.9%（7/181），表现为双阴性（DN；CD4CD8）或 CD8 单阳性（SP）表型，总体存活率均较差。这些病例代表了儿科 T-ALL 的一个亚组，与已知的 T-ALL 亚组在涉及 T 细胞预先承诺、T 细胞身份建立以及β-选择后成熟的基因表达以及突变谱方面存在区别。PU.1 融合蛋白保留转录活性，当在小鼠干细胞/祖细胞中持续表达时，诱导细胞增殖并导致成熟受阻。我们的研究结果强调了 SPI1 融合在高危儿科 T-ALL 中的独特作用。
