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（由适用提供）：以前，我在NCI计划中停产之前获得了两个任期的杰出调查员奖。这些天我继续非常有生产力。我的H指数是179，我是世界上最受欢迎的科学家之一。我在同行评审期刊上发表了1000多篇文章。我还在癌症遗传学方面发现了许多重要发现，并确定并表征了许多癌症基因。我认为，我的发现改变了对癌症的思考方式：Myc癌基因与免疫球蛋白基因座并列及其在Burkitt淋巴瘤中的失调的证明，这是人类癌症特定基因改变的首次演示。 BCL2基因的发现及其参与卵泡淋巴瘤和其他恶性肿瘤。现在，Bcl2蛋白的目标是ABT199，ABT199是Abbott药物，可在CLL患者中完全缓解。 BCl2是控制编程细胞死亡或凋亡的大型基因家族的原型。 All1的发现，现在更名为MLL1，该基因涉及50多个不同的易位。它在癌症中的失调会影响染色质结构。我还发现了AML中ALL1（MLL1）的部分重复。我还发现了TCL1，该TCL1负责98％的人类t细胞白血病，并且该基因在大多数攻击性CLL中都失调。我还发现了涉及T细胞受体在T细胞恶性肿瘤中的易位作用。我还产生了转基因和KO小鼠，以验证我们发现的肿瘤基因和肿瘤抑制基因。人们认为所有癌症基因都在编码蛋白质产品。教条是只有仅占人类基因组2％的蛋白质编码基因很重要，其余98％是“垃圾”。我在2002年发现CLL的发现破坏了这种观点是由于在13q14，miR-15a和miR-16-1上丧失了两个microRNA基因引起的。编码非编码RNA的基因也可以参与癌症发病机理。我们还发现，这两个microRNA靶向Bcl2，即我在1984年发现的基因。我们还发现了人类恶性肿瘤中microRNA基因的种系和体细胞突变，并且在所有癌症中都有microRNA的失调，主要是因为其中一些是负责发病发生的途径的下游靶标。最近，我们发现与巨噬细胞和树突状细胞融合的肺癌和胰腺癌秘密微泡等肿瘤。在这种微泡中包含的miR-21被内在化，到达受体细胞的内体，并结合并激活小鼠中的人类和7个（它的同源物），从而激活受体。然后将NF-κB激活，并分泌IL6和TNFALPHA，从而支持肿瘤扩散和转移性疾病。今年，我们表明微泡与成肌细胞的融合会导致恶病质。