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; CD4^-CD8^-) 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.

中文翻译：

---

复发性SPI1（PU.1）融合在高危儿科T细胞急性淋巴细胞白血病中的应用。

难治性和/或复发性小儿T细胞急性淋巴细胞白血病（T-ALL）的预后极差，其遗传基础尚不十分清楚。在这里，我们报告使用转录组和/或靶向捕获测序对121例儿科T-ALL进行全面分析，通过它们我们鉴定出涉及SPI1的新的复发性基因融合体（STMN1-SPI1和TCF7-SPI1）。例阳性涉及SPI1（编码PU.1）融合体，占的3.9％（181分之7）检测小儿T-ALL的情况下，表现出双阴性（DN; CD4 ^- CD8 ^- ）和CD8 ⁺单阳性（SP）表型，并且总体生存率普遍较差。这些情况代表了儿科T-ALL的一个子集，在涉及T细胞预承诺，T细胞同一性的建立以及β-选择后成熟以及突变情况方面的基因表达方面，与已知的T-ALL子集是有区别的。PU.1融合蛋白保留转录活性，当在小鼠干/祖细胞中组成性表达时，诱导细胞增殖并导致成熟阻滞。我们的发现突出了SPI1融合在高危儿科T-ALL中的独特作用。