T-lineage acute lymphoblastic leukaemia (T-ALL) is a high-risk tumour¹ that has eluded comprehensive genomic characterization, which is partly due to the high frequency of noncoding genomic alterations that result in oncogene deregulation^2,3. Here we report an integrated analysis of genome and transcriptome sequencing of tumour and remission samples from more than 1,300 uniformly treated children with T-ALL, coupled with epigenomic and single-cell analyses of malignant and normal T cell precursors. This approach identified 15 subtypes with distinct genomic drivers, gene expression patterns, developmental states and outcomes. Analyses of chromatin topology revealed multiple mechanisms of enhancer deregulation that involve enhancers and genes in a subtype-specific manner, thereby demonstrating widespread involvement of the noncoding genome. We show that the immunophenotypically described, high-risk entity of early T cell precursor ALL is superseded by a broader category of ‘early T cell precursor-like’ leukaemia. This category has a variable immunophenotype and diverse genomic alterations of a core set of genes that encode regulators of hematopoietic stem cell development. Using multivariable outcome models, we show that genetic subtypes, driver and concomitant genetic alterations independently predict treatment failure and survival. These findings provide a roadmap for the classification, risk stratification and mechanistic understanding of this disease.

T 系急性淋巴细胞白血病 (T-ALL) 是一种高风险肿瘤¹ ，无法进行全面的基因组表征，部分原因是非编码基因组改变频率高，导致癌基因失调^2,3 。在此，我们报告了对 1,300 多名经过统一治疗的 T-ALL 儿童的肿瘤和缓解样本的基因组和转录组测序的综合分析，以及恶性和正常 T 细胞前体的表观基因组和单细胞分析。该方法确定了 15 种具有不同基因组驱动因素、基因表达模式、发育状态和结果的亚型。染色质拓扑分析揭示了增强子失调的多种机制，这些机制以亚型特异性方式涉及增强子和基因，从而证明非编码基因组的广泛参与。我们表明，免疫表型描述的早期 T 细胞前体 ALL 的高风险实体已被更广泛的“早期 T 细胞前体样”白血病类别所取代。该类别具有可变的免疫表型和编码造血干细胞发育调节因子的一组核心基因的多样化基因组改变。使用多变量结果模型，我们表明遗传亚型、驱动因素和伴随的遗传改变独立预测治疗失败和生存。这些发现为该疾病的分类、风险分层和机制理解提供了路线图。