除了已知在T-all中突变的基因外，包括NRAS10,11（n = 3个WGS病例中的n = 3）JAK1（参考文献12，n = 2），Notch1（参考文献13，n = 1），flt3（参考文献14-16，n = 1），n = 1），phf6（phf6（ref。17，n = 3）和wtt1（ref。突变的反复靶标。其中包括DNM2（n = 2），ECT2L（n = 2），EP300（n = 2），GATA3（n = 2），IL7R（n = 2），JAK3（n = 3），reln（n = 2）和runx1（n = 2）和runx1（n = 4）（n = 4）（表1，图1，图2，图2，补充表17和18和18，补充图15）。对于这两种情况，还通过转录组测序（SJTALL002和SJTALL012）分析了38个突变中的21例。我们没有观察到突变等位基因的选择性表达，除了那些伴随野生型等位基因缺失的表达（例如，SJTALL002中的KRAS）。

　　通过Sanger测序和单核苷酸多态性微阵列分析在复发队列中分析的42个基因中，经常突变（补充表19，图2和3A，以及补充图15和16）。在254个经过验证的非塞突变（补充表17）中，40.7％是indel突变，而9.4％是胡说八道突变。与WGS样品中确定的突变相比，预计百分之八十二的错义突变是有害的，这是显着的富集，这与大多数是驾驶员突变一致。

　　我们观察到已知或预测的高频率会导致ETP中的细胞因子受体和RAS信号异常。在64例ETP病例中，有43例（67.2％）在这些途径中有突变，而42例（19％）的非ETP病例中有8例（P< 0.0001; Table 1, Fig. 3b and Supplementary Table 20). Known or predicted activating mutations were identified in BRAF, FLT3, IGFR1, JAK1, JAK3, KRAS and NRAS (Supplementary Results). Three cases harboured the JAK3 M511I mutation located adjacent to the pseudokinase domain that has been identified previously in acute myeloid leukaemia and is transforming when introduced into murine haematopoietic progenitor cells19. The pseudokinase domain mutation, A573V, has previously been identified in acute megakaryoblastic leukaemia and is transforming20. The mutations identified in JAK1 are novel, but are in close proximity to sites of activating mutations previously identified in ALL12.

　　Seven cases (five ETP and two non-ETP) harboured mutations in IL7R encoding the IL7RA (interleukin 7 receptor alpha) chain (Fig. 4a). IL7RA forms a heterodimer with IL2RG (common gamma chain) for the cytokine IL7, and with CRLF2 (cytokine receptor like factor 2) forms a receptor for TSLP (thymic stromal lymphopoietin). IL7R and CRLF2 signalling are important in early lymphoid maturation21. Rearrangement of CRLF2 is observed in B-progenitor ALL22,23, and IL7R mutations have recently been identified in ALL24. All seven cases had an in-frame insertion or substitution at residues I241–V253 of the IL7R transmembrane domain. Consistent with prior data, expression of several of the IL7R mutant alleles in the cytokine-dependent murine haematopoietic Ba/F3 and MOHITO25 cell lines resulted in transformation to cytokine-independent cell growth (Fig. 4b, c). In six cases the mutations introduced a cysteine into the transmembrane domain that induces dimerization of the receptor in the absence of ligand (Fig. 4d). The mutations also induced Stat5 phosphorylation that was attenuated by Jak inhibition (Fig. 4e). expression of mutant, but not wild type Il7r in primary murine haematopoietic progenitors resulted in enhanced colony replating in vitro (Fig. 4f, g), indicating that the IL7R alterations are transforming events in T-ALL.

　　We also identified a high frequency of alterations of genes with roles in haematopoietic and lymphoid development, including RUNX1, IKZF1, ETV6, GATA3 and EP300 (57.8% of ETP cases versus 16.7% of non-ETP T-ALL cases, P < 0.0001). importantly, several of these genes were targeted by multiple mechanisms of alteration across the cohort: sequence mutation, deletion and chromosomal translocations. Six cases (all ETP) had inactivating mutations of GATA3, four of which were biallelic due to either biallelic sequence mutations (SJTALL179, R276Q and A310_T317>VRP;SJTALL010 N286T和S271_W275FS（图2）或由于第二等位基因的伴随删除（补充表18）。GATA3编码GATA结合蛋白3，这是一个高度保守的锌指转录因子的成员，这是早期T-Linege祖细胞的发展所需的，并且在甲状旁腺功能减退症中因感觉神经性耳聋和肾脏肿瘤综合征（HDR）而被突变。在四种情况下，突变为R276，在HDR27中也突变了残基。R276p突变导致GATA3对其DNA靶标的DNA结合亲和力受损，表明在T-ALL中观察到的突变可能是功能的丧失。另一种情况，即SJTALL011，在GATA2，R307W中具有体细胞突变，该突变也位于高度保守的GATA锌指域中，与GATA3 R276W突变同源。

　　十二例（十个ETP和两个非ETP）具有Runx1的变化。两种情况伴随着非突变等位基因的缺失，三个具有Runx1缺失，但没有序列突变。RUNX1是确定的造血率和正常T淋巴发育所必需的，并且通常在髓样和淋巴性恶性肿瘤（补充结果）8,29,30,31,32中重新排列和突变。在T-All中观察到的突变通常涉及Runt结构域，包括移码和废话突变，预计是有害的。9例（八个ETP）具有IKZF1（IKAROS）的缺失或序列突变，该突变编码了所有淋巴样谱系所需的锌指转录因子，这些锌指转录因子通常在高风险的B-progenitor All和T-All的鼠模型中突变为突变（补充图16）。

　　一个值得注意的发现是针对ETP中组蛋白修饰的体细胞改变的高频。六个WGS病例在编码多孔抑制剂复合物2（PRC2）的基因中发生了变化，包括EED，EZH2和SUZ12的缺失和序列突变（表1，图2和补充图17）。EZH2催化组蛋白3赖氨酸27（H3K27）的三甲基化，导致对发育，干细胞维持和分化涉及的基因的转录抑制33。ETP中有27例（42.2％）所有病例都具有这些基因的缺失和/或序列突变，而非ETP T-T-ALL病例中有五个（11.9％）（p = 0.001）。功能收益EZH2 Y641突变在淋巴瘤34中很常见。相比之下，结构建模预测，在T-ALL中观察到的突变可能会破坏催化集合域并导致功能丧失（补充结果和补充图18和19）。此外，SJTALL192的病例还具有SETD2的局灶性纯合缺失，该缺失编码H3K36三甲基酶，另外四个病例具有该基因的功能丧失突变（补充图20）。三个病例预测了组蛋白乙酰转移酶基因EP300（P300）的功能丧失突变。在10例中，有31例ETP和5例非ETP病例具有影响表观遗传调节的突变，它们在10例（9例ETP和1个非ETP）中涉及多个基因。