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

P4 阐明 SYT-SSX 依赖的组蛋白代码改变以指导靶向表观遗传

• 批准号: 8379506
• 负责人: Marc Ladanyi
• 金额: $ 22.86万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8379506
• 关键词: Acute Promyelocytic Leukemia; Address; Binding; Biological; Biological Assay; Biology; Blood specimen; Cancer Etiology; Cell Line; Chimeric Proteins; Chromatin; Chromosomal translocation; Chromosomes, Human, Pair 18; Chronic Myeloid Leukemia; Clinical Data; Clinical Trials; Co-Immunoprecipitations; Correlative Study; DNA; DNA Methylation; DNA Sequence Rearrangement; Data; Data Set; Detection; Enzymes; Epigenetic Process; Etoposide; Event; Funding; Future; Gene Expression; Gene Silencing; Gene Targeting; Genes; Genetic; Genomics; Histone Code; Histone Deacetylase; Histone Deacetylase Inhibitor; Histone deacetylase inhibition; Histones; Human; Imatinib; In Vitro; Intention; Investigation; Lead; Malignant Neoplasms; Maps; Mass Spectrum Analysis; Memorial Sloan-Kettering Cancer Center; Methods; Methylation; Modification; Molecular Profiling; N-terminal; Oncogene Proteins; Outcome; Patients; Pharmacodynamics; Phase; Plasma; Polycomb; Program Research Project Grants; Proteins; Role; Sampling; Silver Staining; Synovial Cell; Synthetic Peptide Libraries; Tail; Therapeutic; Translating; Translational Research; Tretinoin; Validation; Work; X Chromosome; base; bcr-abl Fusion Proteins; design; experience; fusion gene; genome-wide; histone modification; human data; human tissue; inhibitor/antagonist; insight; novel; pre-clinical; promoter; research study; sarcoma; soft tissue; synovial sarcoma; tumor; young adult

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.

滑膜肉瘤（SS）是一种常致死性肉瘤，主要发生于年轻成人