Epigenetic mechanisms of transcriptional activation of a novel oncogenic ALK variant in cancer

癌症中新型致癌 ALK 变体转录激活的表观遗传机制

基本信息

批准号：
10394271
负责人：
Ping Chi
金额：
$ 48.87万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10394271
关键词：
3-Dimensional Adenocarcinoma Cell Algorithms Alleles Automobile Driving BRAF gene Binding Bioinformatics Biological Models CRISPR interference CRISPR/Cas technology Cell Line ChIP-seq Chromatin Chromatin Conformation Capture and Sequencing Chromatin Remodeling Factor Clear cell renal cell carcinoma Clinical Clustered Regularly Interspaced Short Palindromic Repeats Combination immunotherapy Complex Cutaneous Melanoma DNA Data Development Distal Elements Engineering Enhancers Epigenetic Process Extracellular Domain Gene Expression Genomics In Vitro Introns Investigation Kidney Light Lung Lung Adenocarcinoma MAP Kinase Gene MAPK1 gene MEKs Malignant Neoplasms Mediating Melanoma Cell Methodology Modernization Mutate Mutation Nature Nivolumab Normal tissue morphology Oncogene Activation Oncogenes Oncogenic Other Genetics Pathogenesis Patients Phosphotransferases Play Proteins Quality of life RNA Interference Refractory Regulation Regulatory Element Renal Cell Carcinoma Resistance Role Sampling Shapes Signal Pathway Signal Transduction Small Interfering RNA Somatic Mutation Squamous cell carcinoma System Systemic Therapy Technology The Cancer Genome Atlas Therapeutic Transcript Transcription Initiation Transcription Initiation Site Transcriptional Activation Transcriptional Regulation Transmembrane Domain Uveal Melanoma Variant Xenograft procedure cancer type cell immortalization cell transformation chromosome conformation capture clinical investigation clinically relevant crizotinib genome-wide histone modification in vivo inhibitor insight ipilimumab knock-down malignant stomach neoplasm melanoma multidisciplinary mutant novel novel therapeutic intervention promoter recruit standard of care success targeted treatment transcription factor transcriptome sequencing treatment response tumor tumorigenesis

项目摘要

Abstract Comprehensive genomic characterization in cancer has revolutionized our understanding of cancer pathogenesis and provided the scientific rationale for the clinical success of targeted therapies in a variety of cancers. There is emerging evidence that oncogenes activated through epigenetic mechanisms are also important in oncogenic transformation and can dictate therapeutic responses. We recently discovered a novel oncogenic ALK variant, ALKATI, arising through alternative transcription initiation independent of genetic alteration, in 3.4% of all TCGA cancers, including 12% of melanomas and less frequently in other cancer types. The ALKATI can stimulate multiple signaling pathways and is capable of driving oncogenic transformation in immortalized cells in vitro and drive tumorigenesis in vivo. Moreover, engineered ALKATI-transformed cells and tumors, and ALKATI-positive patient derived cell lines and xenografts are sensitive to ALK inhibitors. A patient with ALKATI-positive advanced melanoma who has progressed on standard of care systemic therapy and investigational combination immunotherapy of nivolumab and ipilimumab derived significant clinical benefit from Crizotinib (an ALK inhibitor) with tumor shrinkage and improvement in quality of life. These data have provided the scientific rationale and enthusiasm for the current clinical investigations of ALK-targeted therapies in therapeutic refractory advanced melanoma. ALKATI is not expressed in normal tissues. It is biallelically expressed in tumor samples. These observations, together with the lack of somatic mutations at the ALK locus in the ALKATI-positive tumor samples, indicate that the ALKATI transcriptional activation is through epigenetic mechanisms. Our preliminary data further indicate that MAPK signaling regulates ALKATI expression. Here, we proposes systematic and comprehensive investigations focused on understanding the epigenetic mechanisms in the following three aims: 1) Define the three-dimensional chromatin organization of the long-range interacting elements with the ALKATI transcriptional start site (the ALK-ATI site); 2) Identify and characterize the chromatin modifier(s) involved in ALKATI transcriptional regulation; 3) Elucidate the regulatory mechanisms of ALKATI expression by MAPK signaling in melanoma. We will use modern technologies, including RNA-seq, ChIP-seq, 4C-seq, CRISPR, CRISPR interference (CRISPRi) systems, bioinformatics and integrative analyses, and a repertoire of well-characterized ALKATI-positive and ALKATI-negative cell lines for the proposed multidisciplinary studies. We anticipate that these mechanistic studies will provide insight on not only the basic epigenetic mechanisms in oncogene transcriptional activation through alternative transcription initiation in cancer, but also novel epigenetic therapeutic strategies to target the oncogene transcriptional activation through similar mechanisms.

抽象的癌症中的全面基因组表征彻底改变了我们对癌症的理解发病机理，并为有针对性疗法的临床成功提供了科学原理癌症。有新兴的证据表明，通过表观遗传机制激活的癌基因也是在致癌转化中很重要，可以决定治疗反应。我们最近发现了一本小说致癌碱性变体Alkati，通过替代转录引发而与遗传无关在所有TCGA癌症中，有3.4％的变化，包括12％的黑色素瘤，在其他癌症类型中的频率较低。 Alkati可以刺激多个信号通路，并能够驱动致癌性转化永生的细胞体外并驱动体内肿瘤发生。此外，工程化的Alkati转换细胞和肿瘤和烷阳性阳性患者衍生的细胞系和异种移植物对ALK抑制剂敏感。病人与阿尔卡蒂阳性晚期黑色素瘤有关，他在护理标准的全身疗法和 Nivolumab和ipilimumab的研究组合免疫疗法具有显着的临床益处来自肿瘤收缩和生活质量改善的Crizotinib（一种ALK抑制剂）。这些数据具有提供了科学原理和热情，以实现当前对ALK靶向疗法的临床研究在治疗性难治性晚期黑色素瘤中。阿尔卡蒂在正常组织中未表达。它在肿瘤样品中以双重表达。这些观察，加上Alkati阳性肿瘤样品中ALK基因座缺乏体细胞突变，表明 Alkati转录激活是通过表观遗传机制。我们的初步数据进一步表明 MAPK信号传导调节烷质表达。在这里，我们提出了系统和全面的研究重点是理解以下三个目的中的表观遗传机制：1）定义长距离相互作用元素与Alkati转录的三维染色质组织启动站点（ALK-ATI站点）； 2）识别并表征含有碱的染色质修饰剂转录调节； 3）通过MAPK信号传导阐明Alkati表达的调节机制黑色素瘤。我们将使用现代技术，包括RNA-Seq，Chip-Seq，4C-Seq，CRISPR，CRISPR 干扰（CRISPRI）系统，生物信息学和综合分析以及特征良好的曲目用于拟议的多学科研究的Alkati阳性和烷烃阴性细胞系。我们预料到这一点这些机械研究将不仅提供有关癌基因基本表观遗传机制的见解通过癌症的替代转录开始，但也是新型表观遗传学的转录激活通过类似机制靶向癌基因转录激活的治疗策略。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Charles David Allis (1951-2023).

查尔斯·大卫·艾利斯（1951-2023）。

DOI：
10.1038/s41588-023-01331-z
发表时间：
2023
期刊：
Nature genetics
影响因子：
30.8
作者：
Chi,Ping;Lewis,PeterW;Lu,Chao;Lu,Janice;Ruthenburg,AlexanderJ;Sabari,BenjaminR;Shechter,David;Wan,Liling;Wang,GangGreg
通讯作者：
Wang,GangGreg

GNA11 Q209L Mouse Model Reveals RasGRP3 as an Essential Signaling Node in Uveal Melanoma.

DOI：
10.1016/j.celrep.2020.108277
发表时间：
2020-10-13
期刊：
Cell reports
影响因子：
8.8
作者：
Moore AR;Ran L;Guan Y;Sher JJ;Hitchman TD;Zhang JQ;Hwang C;Walczak EG;Shoushtari AN;Monette S;Murali R;Wiesner T;Griewank KG;Chi P;Chen Y
通讯作者：
Chen Y

Clinical genomic profiling in the management of patients with soft tissue and bone sarcoma.

DOI：
10.1038/s41467-022-30496-0
发表时间：
2022-06-15
期刊：
Nature communications
影响因子：
16.6
作者：
通讯作者：

Direct evidence that the GPCR CysLTR2 mutant causative of uveal melanoma is constitutively active with highly biased signaling.

DOI：
10.1074/jbc.ra120.015352
发表时间：
2021-01
期刊：
The Journal of biological chemistry
影响因子：
0
作者：
Ceraudo E;Horioka M;Mattheisen JM;Hitchman TD;Moore AR;Kazmi MA;Chi P;Chen Y;Sakmar TP;Huber T
通讯作者：
Huber T