Cancer Gene Discovery to Identify Targetable Targets

癌症基因发现以确定可靶向的靶点

基本信息

批准号：
9321279
负责人：
CARLO M CROCE
金额：
$ 92.4万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-11 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9321279
关键词：
13q14 Affect Apoptosis Award BCL-2 Protein BCL2 gene Binding Burkitt Lymphoma Cachexia Cells Chromatin Structure Chromosomes Code DNA Sequence Alteration Dendritic Cells Disease Endosomes Follicular Lymphoma Gene Family Gene Mutation Genes Germ-Line Mutation Homologous Gene Human Human Genome IL6 gene Immunoglobulins In complete remission Journals Knockout Mice MLL gene MYC gene Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of pancreas MicroRNAs Mus Mutation Myoblasts Oncogenes Pathogenesis Pathway interactions Patients Peer Review Pharmaceutical Preparations Proteins Publishing Research Personnel Role Scientist Somatic Mutation T-Cell Leukemia T-Cell Receptor T-Lymphocyte TLR8 gene Transgenic Mice Tumor Suppressor Genes Untranslated RNA Work cancer genetics gene discovery indexing macrophage microvesicles novel programs prototype public health relevance receptor tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Previously, I was awarded the Outstanding Investigator award for two terms before the Program at NCI was discontinued. I have continued to be extremely productive to these days. My H index is 179 and I am one of the most cited scientists in the world. I have published more than 1000 articles in peer reviewed journals. I have also made many important discoveries in cancer genetics and have identified and characterized many cancer genes. My discoveries that changed the ways to think about cancer, I believe, are: the demonstration of the juxtaposition of the MYC oncogene to the immunoglobulin loci and its dysregulation in Burkitt lymphoma, the first demonstration of the specific gene alterations in human cancer. The discovery of the BCL2 gene and its involvement in follicular lymphoma and in other malignancies. The Bcl2 protein is now targeted by ABT199, a drug of Abbott that causes complete remission in patients with CLL. BCL2 is the prototype of a large family of genes that control programmed cell death, or apoptosis. The discovery of ALL1, now renamed MLL1, a gene involved in more than 50 different translocations in ALL and AML. Its dysregulation in cancer affects chromatin structure. I also discovered the partial duplication of ALL1 (MLL1) in AML. I also discovered TCL1, which is responsible for 98% of human pre T cell leukemias, and that this gene is dysregulated in most of the aggressive CLLs. I have also discovered the role of translocations involving the T cell receptor in T cell malignancies. I also generated transgenic and KO mice to validate the oncogenes and tumor suppressor genes we discovered. It was thought that all cancer genes were encoding protein products. The dogma was that only protein coding genes that represent only 2% of the human genome were important and the remaining 98% was "junk". This view was shattered by my discovery in 2002 that CLL is caused by the loss of two microRNA genes on chromosome 13q14, miR-15a and miR-16-1. Thus genes encoding non coding RNAs can also be involved in cancer pathogenesis. We also found that these two microRNAs target BCL2, the gene I discovered in 1984. We also discovered germline and somatic mutations in microRNA genes in human malignancies and that microRNAs are dysregulated in all cancers, primarily because several of them are downstream targets of pathways responsible for oncogenesis. More recently, we discovered that tumors such as lung cancer and pancreatic cancer secrete microvesicles that fuse with macrophages and dendritic cells. MiR-21 that is contained in such microvesicles is internalized, reaches the endosomes of the recipient cells and binds and activates Toll Like Receptor 8 in humans and 7 (it's homologue) in the mouse, activating the receptor. Then NF-κB is activated and IL6 and TNFalpha are secreted, facilitating tumor spreading and metastatic disease. This year we showed that fusion of microvesicles with myoblasts causes cachexia.

描述（由申请人提供）：此前，在 NCI 项目终止之前，我曾获得过两个学期的杰出研究者奖，至今我的 H 指数仍然非常高，是最高的研究者之一。我在同行评审期刊上发表了 1000 多篇文章，在癌症遗传学方面也取得了许多重要发现，并鉴定和表征了许多癌症基因。我认为，癌症是：在伯基特淋巴瘤中证明了 MYC 癌基因与免疫球蛋白基因座的并置及其失调，首次证明了人类癌症中的特定基因改变，发现了 BCL2 基因及其与滤泡的关系。 Bcl2 蛋白现在是 ABT199 的靶标，ABT199 是雅培公司的一种药物，可以使 BCL2 患者完全缓解。控制程序性细胞死亡或细胞凋亡的基因家族的发现，现已更名为 MLL1，该基因参与 ALL 和 AML 中的 50 多种不同易位，它在癌症中的失调会影响染色质结构。 AML 中的 ALL1 (MLL1) 我还发现了 TCL1，它导致 98% 的人类前 T 细胞白血病，并且该基因在大多数侵袭性 CLL 中失调。我还发现了 T 细胞恶性肿瘤中涉及 T 细胞受体的易位的作用，我还生成了转基因小鼠和 KO 小鼠来验证我们发现的癌基因和肿瘤抑制基因。我认为只有占人类基因组 2% 的蛋白质编码基因才是重要的，其余 98% 都是“垃圾”，2002 年我发现 CLL 是由两个基因的缺失引起的，这一观点被打破了。染色体 13q14 上的 microRNA 基因、miR-15a 和 miR-16-1 因此，编码非编码 RNA 的基因也可能参与癌症发病机制。我们还发现这两种 microRNA 靶向 BCL2，这是我在 1984 年发现的基因。人类恶性肿瘤中 microRNA 基因的种系和体细胞突变，以及 microRNA 在所有癌症中都失调，主要是因为其中一些是负责肿瘤发生的途径的下游靶标。我们发现肺癌和胰腺癌等肿瘤会分泌与巨噬细胞融合的微泡，这些微泡中包含的 MiR-21 被内化，到达受体细胞的内体并结合并激活人类的 Toll 样受体 8。和 7（它的同源物）在小鼠体内激活受体，然后 NF-κB 被激活，IL6 和 TNFα 被分泌，从而促进。今年，我们发现微泡与成肌细胞的融合会导致恶病质。