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.

抽象的 随着个性化癌症医学的出现，肿瘤中的突变可以与靶向疗法配对 例如酪氨酸激酶抑制剂（TKI）。但是，即使是最有效的TKI也无法消除所有癌细胞。 随后，最小残留疾病（MRD）中的肿瘤抑制细胞有助于患者复发。 在慢性粒细胞性白血病（CML）中，将ABL激酶抑制剂应用于BCR/ABL癌蛋白是 个性化医学范式。 CML中的TKI疗法可带来持久的治疗益处；然而， MRD仍然存在，并最终可能发展为爆炸危机。尽管分子机制是 TKI失败根除CML MRD尚不清楚，怀疑生长因子信号以取代TKI- 残疾癌蛋白存活信号。我们已经确定C-FOS和DUSP1对于生长因素 - 介导的TKI抗性。 DUSP1和C-FOS的遗传和化学抑制作用使CML精确地呈现CML 对TKI敏感，并治愈CML的小鼠模型。总体而言，我们已发表的初步数据表明 C-FOS和DUSP1的表达水平决定了慢性CML疾病期间TKI功效的阈值。 扩展了这一调查，拟议的研究将确定C-FOS和DUSP1是否是 必要和足够的CML演变以爆破危机，以及C-FOS和DUSP1水平是否 确定爆炸危机中对TKI的反应。接下来，我们假设FOS和DUSP1信号会汇聚 致激活的增强子。我们建议FOS-JUN AP-1复合物有助于肿瘤活跃 增强剂，而在没有C-FOS和DUSP1信号的情况下，Jun-Jund AP-1复合物占主导 不支持肿瘤维护。具体而言，我们将分子将C-FOS-JUN AP-1和DUSP1活性联系到 全局增强剂染色质动力学。此外，我们将利用与染色质的靶标为基因培养基 等位基因以在初级的单细胞水平上提供与功能相关的下游基因的详细分析 CML细胞。预计拟议的工作将描述CML-Blast-Crisis中C-Fos和Dusp1的必要性 TKI敏感性，以及对爆炸危机背后的机制的深刻洞察力和 细胞因子介导的TKI抗性。我们希望此信息不仅对CML和 爆炸危机，也是未用TKI治愈的广泛的酪氨酸激酶癌蛋白驱动的肿瘤。