P4 Elucidating SYT-SSX-depend histone code alterations to guide targeted epigenet

滑膜肉瘤（SS）是一种主要发生于年轻人的致命性肉瘤， 特异性染色体易位，t（X;18），其将18号染色体上的SYT基因融合到 X染色体上的SSX 1或SSX 2基因。SYT-SSX融合癌蛋白的功能异常， 转录蛋白，SYT-SSX通过与组蛋白修饰物相互作用来发挥其转录作用。 酶，导致基因表达的表观遗传控制的失调。目前的建议带来了 结合基础组蛋白密码生物学的专业知识和滑膜肉瘤细胞系的经验， 基于人类组织的转化研究，以更深入地了解SYT-SSX依赖性 组蛋白编码的改变，可能会导致更合理，更精确的目标，并希望，更多 滑膜肉瘤有效的表观遗传学治疗。拟议的工作解决了SYTSSX的核心作用- 滑膜肉瘤生物学中的依赖性表观遗传改变来自三种互补的 观点：机制（目标1），全球基因组（目标2）和临床前（目标3）。 某些癌症被认为是由基因重排引起的，这种重排将单独的基因连接起来，产生新的 功能异常的融合基因。滑膜肉瘤中的SYT-SSX融合基因就是这样一种基因。 了解和靶向这些致癌融合基因所使用的生物学机制， 导致有效的治疗，如靶向慢性髓细胞性白血病中BCR-ABL的伊马替尼所例示的 白血病和靶向PML-RAR α的全反式维甲酸治疗急性早幼粒细胞白血病。

Synovial sarcoma (SS), an often lethal sarcoma occurring predominantly in young adults, is defined by a specific chromosomal translocation, t(X;18), which fuses the SYT gene on chromosome 18 to either the SSXl or the SSX2 gene on chromosome X. The SYT-SSX fusion oncoprotein functions as aberrant transcriptional protein that SYT-SSX exerts its transcriptional effects by interacting with histone-modifying enzymes, leading to a deregulation of epigenetic control of gene expression. The present proposal brings together expertise in fundamental histone code biology with experience in synovial sarcoma cell line- and human tissue-based translational research to develop a deeper understanding of SYT-SSX-dependent histone code alterations that could lead to more rational, more precisely targeted, and, hopefully, more effective epigenetic therapy for synovial sarcoma. The proposed work addresses the central role of SYTSSX- dependent epigenetic alterations in the biology of synovial sarcoma from three complementary perspectives: mechanistic (Aim 1), global genomic (Aim 2), and preclinical (Aim 3). Certain cancers are thought to arise from genetic rearrangements that join separate genes to produce new fusion genes with abnormal functions. The SYT-SSX fusion gene in synovial sarcoma is such a gene. Understanding and targeting the biological mechanisms used by these cancer-causing fusion genes can lead to effective therapeutics, as exemplified by imatinib targeting BCR-ABL in chronic myelogenous leukemia and all-trans retinoic acid targeting PML-RARa in acute promyelocytic leukemia.