Cellular transformation is accompanied by extensive rewiring of many biological processes leading to augmented levels of distinct types of cellular stress, including proteotoxic stress. Cancer cells critically depend on stress-relief pathways for their survival. However, the mechanisms underlying the transcriptional initiation and maintenance of the oncogenic stress response remain elusive. Here, we show that the expression of heat shock transcription factor 1 (HSF1) and the downstream mediators of the heat shock response is transcriptionally upregulated in T cell acute lymphoblastic leukemia (T-ALL). Hsf1 ablation suppresses the growth of human T-ALL and eradicates leukemia in mouse models of T-ALL, while sparing normal hematopoiesis. HSF1 drives a compact transcriptional program and among the direct HSF1 targets, specific chaperones and co-chaperones mediate its critical role in T-ALL. Notably, we demonstrate that the central T-ALL oncogene NOTCH1 hijacks the cellular stress response machinery by inducing the expression of HSF1 and its downstream effectors. The NOTCH1 signaling status controls the levels of chaperone/co-chaperone complexes and predicts the response of T-ALL patient samples to HSP90 inhibition. Our data demonstrate an integral crosstalk between mediators of oncogene and non-oncogene addiction and reveal critical nodes of the heat shock response pathway that can be targeted therapeutically.

中文翻译：

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T细胞急性淋巴细胞白血病中应激反应机制的致癌劫持。

细胞转化伴随着许多生物过程的广泛重新布线，导致不同类型的细胞应激（包括蛋白毒性应激）水平提高。癌细胞的生存关键取决于缓解压力的途径。然而，致癌应激反应的转录起始和维持的基础机制仍然难以捉摸。在这里，我们显示热休克转录因子1（HSF1）和热休克反应的下游介质的表达在T细胞急性淋巴细胞白血病（T-ALL）中转录上调。Hsf1消融抑制了T-ALL小鼠的生长并消除了T-ALL小鼠模型中的白血病，同时保留了正常的造血功能。HSF1驱动一个紧凑的转录程序，在直接的HSF1目标中，特定的伴侣和伴侣伴侣在T-ALL中起关键作用。值得注意的是，我们证明了中央T-ALL癌基因NOTCH1通过诱导HSF1及其下游效应子的表达劫持了细胞应激反应机制。NOTCH1信号状态控制着伴侣/共伴侣复合物的水平，并预测了T-ALL患者样品对HSP90抑制的反应。我们的数据证明了致癌基因和非致癌基因上瘾者之间的整体串扰，并揭示了可用于治疗的热休克反应途径的关键节点。NOTCH1信号状态控制着伴侣/共伴侣复合物的水平，并预测了T-ALL患者样品对HSP90抑制的反应。我们的数据表明致癌基因和非致癌基因成瘾者之间存在着不可分割的串扰，并揭示了可用于治疗的热休克反应途径的关键节点。NOTCH1信号状态控制着伴侣/共伴侣复合物的水平，并预测了T-ALL患者样品对HSP90抑制的反应。我们的数据表明致癌基因和非致癌基因成瘾者之间存在着不可分割的串扰，并揭示了可用于治疗的热休克反应途径的关键节点。