Genetic alterations that activate NOTCH1 signaling and T cell transcription factors, coupled with inactivation of the INK4/ARF tumor suppressors, are hallmarks of T-lineage acute lymphoblastic leukemia (T-ALL), but detailed genome-wide sequencing of large T-ALL cohorts has not been carried out. Using integrated genomic analysis of 264 T-ALL cases, we identified 106 putative driver genes, half of which had not previously been described in childhood T-ALL (for example, CCND3, CTCF, MYB, SMARCA4, ZFP36L2 and MYCN). We describe new mechanisms of coding and noncoding alteration and identify ten recurrently altered pathways, with associations between mutated genes and pathways, and stage or subtype of T-ALL. For example, NRAS/FLT3 mutations were associated with immature T-ALL, JAK3/STAT5B mutations in HOXA1 deregulated ALL, PTPN2 mutations in TLX1 deregulated T-ALL, and PIK3R1/PTEN mutations in TAL1 deregulated ALL, which suggests that different signaling pathways have distinct roles according to maturational stage. This genomic landscape provides a logical framework for the development of faithful genetic models and new therapeutic approaches.

中文翻译：

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儿科和年轻成人T系急性淋巴细胞白血病的基因组景观。

激活NOTCH1信号和T细胞转录因子的基因改变，以及INK4 / ARF肿瘤抑制因子的失活，是T系急性淋巴细胞白血病（T-ALL）的标志，但对大型T-ALL人群进行了详细的全基因组测序尚未进行。通过对264个T-ALL病例进行综合基因组分析，我们确定了106个推定的驱动基因，其中一半以前在儿童T-ALL中没有描述过（例如CCND3，CTCF，MYB，SMARCA4，ZFP36L2和MYCN）。我们描述了编码和非编码改变的新机制，并确定了十个反复改变的途径，以及突变基因和途径与T-ALL的阶段或亚型之间的关联。例如，NRAS / FLT3突变与HOXA1失控的ALL中未成熟的T-ALL，JAK3 / STAT5B突变相关，TLX1中的PTPN2突变使T-ALL失控，而TAL1中的PIK3R1 / PTEN突变使ALL失控，这表明不同的信号通路根据成熟阶段具有不同的作用。这种基因组格局为忠实的遗传模型和新的治疗方法的发展提供了逻辑框架。