Ludwig Institute for Cancer Research, Brussels Branch, Belgium; de Duve Institute, Université Catholique de Louvain, Brussels, Belgium;
Istituto Superiore di Sanità, Rome, Italy; and.
Blood. 2014 Dec 18;124(26):3924-31. doi: 10.1182/blood-2014-05-576652. Epub 2014 Oct 28.
The acquisition of growth signal self-sufficiency is 1 of the hallmarks of cancer. We previously reported that the murine interleukin-9-dependent TS1 cell line gives rise to growth factor-independent clones with constitutive activation of the Janus kinase (JAK)- signal transducer and activator of transcription (STAT) pathway. Here, we show that this transforming event results from activating mutations either in JAK1, JAK3, or in both kinases. Transient and stable expression of JAK1 and/or JAK3 mutants showed that each mutant induces STAT activation and that their coexpression further increases this activation. The proliferation of growth factor-independent TS1 clones can be efficiently blocked by JAK inhibitors such as ruxolitinib or CMP6 in short-term assays. However, resistant clones occur upon long-term culture in the presence of inhibitors. Surprisingly, resistance to CMP6 was not caused by the acquisition of secondary mutations in the adenosine triphosphate-binding pocket of the JAK mutant. Indeed, cells that originally showed a JAK1-activating mutation became resistant to inhibitors by acquiring another activating mutation in JAK3, whereas cells that originally showed a JAK3-activating mutation became resistant to inhibitors by acquiring another activating mutation in JAK1. These observations underline the cooperation between JAK1 and JAK3 mutants in T-cell transformation and represent a new mechanism of acquisition of resistance against JAK inhibitors.
获得生长信号自给自足是癌症的标志之一。我们之前报道过，鼠白细胞介素-9 依赖性 TS1 细胞系产生具有组成性激活 Janus 激酶 (JAK)-信号转导和转录激活因子 (STAT) 途径的生长因子非依赖性克隆。在这里，我们表明，这种转化事件是由于 JAK1、JAK3 或两种激酶中的激活突变引起的。JAK1 和/或 JAK3 突变体的瞬时和稳定表达表明每种突变体均可诱导 STAT 激活，并且它们的共表达进一步增加了这种激活。在短期测定中，生长因子非依赖性 TS1 克隆的增殖可以被 JAK 抑制剂（如鲁索替尼或 CMP6）有效阻断。然而，在抑制剂存在下长期培养会出现耐药克隆。令人惊讶的是，对 CMP6 的耐药性不是由于 JAK 突变体腺苷三磷酸结合口袋中的继发突变获得引起的。事实上，最初显示 JAK1 激活突变的细胞通过在 JAK3 中获得另一个激活突变而对抑制剂产生耐药性，而最初显示 JAK3 激活突变的细胞通过在 JAK1 中获得另一个激活突变而对抑制剂产生耐药性。这些观察结果强调了 JAK1 和 JAK3 突变体在 T 细胞转化中的合作，并代表了对 JAK 抑制剂获得耐药性的新机制。
