Mechanism of non-oncogene addiction

非癌基因成瘾机制

• 批准号: 10091403
• 负责人: Mohammad Azam
• 金额: $ 36.37万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-15 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10091403
• 关键词: Accelerated Phase; Acute leukemia; Affect; Alleles; Applications Grants; Basic Science; Binding; Blast Phase; Cells; Chemicals; Chromatin; Chronic; Chronic Myeloid Leukemia; Chronic Phase; Clinical; Complex; Data; Development; Diagnosis; Disabled Persons; Disease; EVI1 gene; Enhancers; Epigenetic Process; Evolution; FOS gene; Failure; Genes; Genetic; Growth Factor; HOXA9 gene; Histone H3; Histones; Indolent; Internal Ribosome Entry Site; Investigation; Knowledge; Link; MAP Kinase Gene; Maintenance; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Mediating; Mediator of activation protein; Medicine; Modality; Modeling; Molecular; Mutation; NUP98 gene; Nature; Oncogenic; Oncoproteins; Organ; Patients; Phase; Protein Tyrosine Kinase; Publishing; RUNX1 gene; Reporter; Reporter Genes; Research; Residual Neoplasm; Resistance; Signal Transduction; Solid; Solid Neoplasm; TP53 gene; Testing; Therapeutic; Transcription Factor AP-1; Tyrosine Kinase Inhibitor; Work; bcr-abl Fusion Proteins; cancer cell; chronic myeloid leukemia cell; cytokine; insight; kinase inhibitor; leukemia; leukemic transformation; malignant breast neoplasm; mortality; mouse model; novel therapeutics; overexpression; p38 Mitogen Activated Protein Kinase; paracrine; personalized medicine; refractory cancer; relapse patients; response; stem cells; targeted treatment; transcription factor; tumor

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.

摘要 随着个性化癌症药物的出现，肿瘤中的突变可以与靶向治疗配对 例如酪氨酸激酶抑制剂（TKI）。然而，即使是最有效的TKI也无法根除所有癌细胞。 随后，微小残留病（MRD）内的肿瘤重建细胞有助于患者复发。 BCR/ABL癌蛋白激酶抑制剂在慢性粒细胞白血病（CML）中的应用 个性化医疗的典范TKI治疗CML可带来持久的治疗获益;然而， MRD仍然存在，并最终可能演变为爆炸危机。尽管这些疾病的分子机制 TKI未能根除CML MRD尚不清楚，怀疑生长因子信号替代TKI- 使癌蛋白存活信号失效。我们已经确定c-Fos和Dusp 1对生长因子- 介导的TKI耐药性。Dusp 1和c-Fos的遗传和化学抑制使CML变得精致 对TKI敏感，对CML小鼠模型有治疗作用。总的来说，我们公布的和初步的数据表明， c-Fos和Dusp 1的表达水平决定了慢性CML疾病期间TKI疗效的阈值。 延伸这条调查路线，拟议的研究将确定c-Fos和Dusp 1是否是 c-Fos和Dusp 1水平是否是CML向急变演变的必要和充分条件， 确定在爆炸危机中对TKI的反应。接下来，我们假设Fos和Dusp 1信号收敛于 致癌激活的增强子。我们认为Fos-Jun AP-1复合物促进致癌活性 增强子，而在c-Fos和Dusp 1信号不存在的情况下，Jun-JunD AP-1复合物占主导地位，但 不支持肿瘤维持。具体来说，我们将c-Fos-Jun AP-1和Dusp 1活性分子连接到 全局增强子染色质动力学。此外，我们还将开发染色质包埋的靶基因报告基因 等位基因，以在原代细胞中在单细胞水平上提供功能相关下游基因的详细分析。 CML细胞。拟议的工作预计将阐明c-Fos和Dusp 1在CML爆炸危机中的必要性 TKI敏感性，以及提供深入的分子洞察基础的机制爆炸危机， 苦参碱介导的TKI耐药性。我们预计这些信息不仅对CML， 原始细胞危象，但也广泛组酪氨酸激酶癌蛋白驱动的肿瘤，不能治愈的TKI。