Mechanism of non-oncogene addiction

摘要 随着个性化癌症药物的出现，肿瘤的突变可以与靶向治疗相结合。 例如酪氨酸激酶抑制剂(TKI)。然而，即使是最有效的TKI也无法根除所有的癌细胞。 随后，微小残留病(MRD)内的肿瘤再生细胞有助于患者复发。 Abl-激酶抑制剂在慢性粒细胞白血病bcr/abl癌蛋白中的应用 个性化医疗的典范。慢性粒细胞白血病的TKI疗法带来了持久的治疗益处；然而， MRD仍然存在，并最终可能演变为爆炸性危机。尽管潜在的分子机制 将军澳未能根除CML MRD尚不得而知，生长因子信号可能取代TKI- 癌蛋白生存信号失效。我们已经确定c-Fos和DUSP1对生长因子- 介导的TKI抵抗。DUSP1和c-Fos的遗传和化学抑制使CML变得微妙 对TKI敏感，并治愈CML小鼠模型。总体而言，我们公布的和初步的数据表明 C-Fos和DUSP1的表达水平决定了慢性CML患者TKI疗效的阈值。 延伸这一调查范围，拟议的研究将确定c-Fos和DUSP1是否 C-Fos和DUSP1水平是CML演变为BLAST危机的充要条件 确定在爆炸危机中对TKI的反应。接下来，我们假设Fos和DUSP1信号会聚在 致癌激活的增强剂。我们认为Fos-Jun AP-1复合体促进肿瘤活性 在没有c-Fos和DUSP1信号的情况下，Jun-Jund AP-1复合体占优势 不支持肿瘤的维护。具体地说，我们将c-Fos-jun AP-1和DUSP1的活性从分子上联系到 全球增强子染色质动力学。此外，我们还将开发染色质嵌入的靶基因报告程序 等位基因，在单细胞水平上提供功能相关的下游基因的详细分析 慢性粒细胞白血病细胞。这项拟议的工作有望阐明c-Fos和DUSP1在CML-BLAST危机中的必要性 TKI敏感性，以及提供对爆炸危机和 细胞因子介导的TKI耐药。我们希望这些信息不仅对CML和 白血病危机，但也包括广泛的酪氨酸激酶癌蛋白驱动的肿瘤，这些肿瘤不能通过TKI治愈。

Abstract With the advent of personalized cancer medicine, mutations in tumors can be paired with targeted therapies such as tyrosine kinase inhibitors (TKI). However, even the most potent TKI fail to eradicate all cancer cells. Subsequently, tumor-repopulating cells within minimal residual disease (MRD) contribute to patient relapse. The application of Abl-kinase inhibitors to the BCR/ABL oncoprotein in chronic myelogenous leukemia (CML) is a paradigm for personalized medicine. TKI therapy in CML leads to long lasting therapeutic benefit; however, MRD remains and can eventually evolve to blast crisis. Although the molecular mechanisms underlying the failure of TKI to eradicate CML MRD are not known, growth factor signals are suspected to replace the TKI- disabled oncoprotein survival signals. We have determined that c-Fos and Dusp1 are critical for growth-factor- mediated TKI resistance. Both genetic and chemical inhibition of Dusp1 and c-Fos render CML exquisitely sensitive to TKI, and cure a mouse model of CML. Overall, our published and preliminary data suggests that expression levels of c-Fos and Dusp1 determine the threshold of TKI efficacy during chronic CML disease. Extending this line of investigation, the proposed research will determine whether c-Fos and Dusp1 are necessary and sufficient for the evolution of CML to blast crisis, and whether c-Fos and Dusp1 levels determine response to TKI in blast crisis. Next, we hypothesize that Fos and Dusp1 signals converge upon oncogenically-activated enhancers. We propose that Fos-Jun AP-1 complexes facilitate oncogenically active enhancers, while in the absence of c-Fos and Dusp1 signals, Jun-JunD AP-1 complexes predominate but do not support tumor maintenance. Specifically, we will molecularly link c-Fos-Jun AP-1 and Dusp1 activity to global enhancer chromatin dynamics. Moreover, we will exploit chromatin-embedded target-gene-reporter alleles to provide a detailed analysis of functionally-relevant downstream genes at a single-cell level in primary CML cells. The proposed work is expected to delineate the necessity of c-Fos and Dusp1 in CML-blast-crisis TKI sensitivity, as well as to provide deep molecular insight into the mechanisms underlying blast crisis and cytokine-mediated TKI resistance. We expect that this information will be informative not only for CML and blast crisis, but also the broad group of tyrosine-kinase oncoprotein-driven tumors that are not cured by TKI.