Cancer Gene Discovery to Identify Targetable Targets

癌症基因发现以确定可靶向的靶点

• 批准号: 9763332
• 负责人: CARLO M CROCE
• 金额: $ 89.63万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 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/9763332
• 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

 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）：以前，我被授予杰出的研究者奖两个任期之前，该计划在NCI被中止。这些天来，我一直非常富有成效。我的H指数是179，我是世界上被引用次数最多的科学家之一。我在同行评审的期刊上发表了1000多篇文章。 我在癌症遗传学方面也有许多重要发现，并鉴定和描述了许多癌症基因。我相信，我的发现改变了人们对癌症的看法，这些发现是：在伯基特淋巴瘤中，MYC癌基因与免疫球蛋白基因座并置及其失调的证明，这是人类癌症中特异性基因改变的第一个证明。BCL 2基因的发现及其在滤泡性淋巴瘤和其他恶性肿瘤中的作用Bcl 2蛋白现在被Abbott的药物ABT 199靶向，该药物可使CLL患者完全缓解。BCL 2是控制程序性细胞死亡或凋亡的基因大家族的原型。ALL 1的发现，现在更名为MLL 1，这是一种涉及ALL和AML中50多种不同易位的基因。它在癌症中的失调影响染色质结构。我还发现了AML中ALL 1（MLL 1）的部分重复。我还发现了TCL 1，它是98%的人类前T细胞白血病的原因，并且该基因在大多数侵袭性CLL中失调。我还发现了涉及T细胞受体的易位在T细胞恶性肿瘤中的作用。我还制造了转基因和KO小鼠来验证我们发现的癌基因和肿瘤抑制基因。 人们认为所有的癌症基因都编码蛋白质产物。当时的教条是，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是由染色体13 q14上的两个microRNA基因（miR-15 a和miR-16-1）丢失引起的，这一发现粉碎了这种观点。因此，编码非编码RNA的基因也可以参与癌症发病机制。我们还发现这两种microRNA靶向BCL 2，这是我在1984年发现的基因。我们还发现了人类恶性肿瘤中microRNA基因的生殖系和体细胞突变，并且microRNA在所有癌症中均失调，主要是因为其中一些是负责肿瘤发生的途径的下游靶点。最近，我们发现肺癌和胰腺癌等肿瘤分泌的微泡与巨噬细胞和树突状细胞融合。包含在这种微泡中的miR-21被内化，到达受体细胞的内体，并结合并激活人类中的Toll样受体8和小鼠中的Toll样受体7（其同源物），从而激活受体。然后NF-κB被激活，IL 6和TNF α分泌，促进肿瘤扩散和转移性疾病。今年我们发现微泡与成肌细胞的融合导致恶病质。