Malignant transformation of cells typically involves several genetic lesions, whose combined activity gives rise to cancer 1 . Here we analyse 1,148 patient-derived B-cell leukaemia (B-ALL) samples, and find that individual mutations do not promote leukaemogenesis unless they converge on one single oncogenic pathway that is characteristic of the differentiation stage of transformed B cells. Mutations that are not aligned with this central oncogenic driver activate divergent pathways and subvert transformation. Oncogenic lesions in B-ALL frequently mimic signalling through cytokine receptors at the pro-B-cell stage (via activation of the signal-transduction protein STAT5) 2 – 4 or pre-B-cell receptors in more mature cells (via activation of the protein kinase ERK) 5 – 8 . STAT5- and ERK-activating lesions are found frequently, but occur together in only around 3% of cases ( P = 2.2 × 10 −16 ). Single-cell mutation and phospho-protein analyses reveal the segregation of oncogenic STAT5 and ERK activation to competing clones. STAT5 and ERK engage opposing biochemical and transcriptional programs that are orchestrated by the transcription factors MYC and BCL6, respectively. Genetic reactivation of the divergent (suppressed) pathway comes at the expense of the principal oncogenic driver and reverses transformation. Conversely, deletion of divergent pathway components accelerates leukaemogenesis. Thus, persistence of divergent signalling pathways represents a powerful barrier to transformation, while convergence on one principal driver defines a central event in leukaemia initiation. Pharmacological reactivation of suppressed divergent circuits synergizes strongly with inhibition of the principal oncogenic driver. Hence, reactivation of divergent pathways can be leveraged as a previously unrecognized strategy to enhance treatment responses. Analysis of B-cell leukaemia samples reveals that oncogenic mutations do not cause malignant transformation unless they converge on the same signalling pathway, and that it may be possible clinically to combine inhibition of the principal oncogenic driver with reactivation of divergent pathways.

中文翻译：

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来自不同途径的信号输入颠覆了 B 细胞转化

细胞的恶性转化通常涉及几个遗传病变，其联合活动会导致癌症 1。在这里，我们分析了 1,148 份源自患者的 B 细胞白血病 (B-ALL) 样本，发现单个突变不会促进白血病生成，除非它们集中在一个单一的致癌途径上，该途径是转化 B 细胞分化阶段的特征。与这个中心致癌驱动因素不一致的突变会激活不同的途径并破坏转化。B-ALL 中的致癌病变经常模拟通过前 B 细胞阶段的细胞因子受体（通过激活信号转导蛋白 STAT5）2-4 或更成熟细胞中的前 B 细胞受体（通过激活蛋白激酶 ERK) 5 – 8 。经常发现 STAT5 和 ERK 激活病变，但仅在大约 3% 的情况下同时发生（ P = 2.2 × 10 -16 ）。单细胞突变和磷蛋白分析揭示了致癌 STAT5 和 ERK 激活与竞争克隆的分离。STAT5 和 ERK 分别参与由转录因子 MYC 和 BCL6 协调的相反的生化和转录程序。发散（被抑制）途径的遗传再激活是以牺牲主要致癌驱动因素和逆转转化为代价的。相反，不同途径成分的缺失会加速白血病生成。因此，不同信号通路的持续存在代表了转化的强大障碍，而一个主要驱动因素的融合定义了白血病起始的中心事件。抑制发散回路的药理学重新激活与主要致癌驱动因素的抑制产生强烈的协同作用。因此，可以利用重新激活不同途径作为一种以前未被认识的策略来增强治疗反应。B 细胞白血病样本的分析表明，致癌突变不会导致恶性转化，除非它们聚集在同一信号通路上，并且临床上可能将主要致癌驱动因素的抑制与不同通路的重新激活相结合。