Histone Modification and Transcription Elongation in Human Cancer

人类癌症中的组蛋白修饰和转录延伸

• 批准号: 9763342
• 负责人: EDWIN R SMITH
• 金额: $ 18.54万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-19 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9763342
• 关键词: Acute; Acute Lymphocytic Leukemia; C-terminal; Childhood Leukemia; Chimera organism; Chimeric Proteins; Chromatin; Chromatin Remodeling Factor; Chromosomal Rearrangement; Chromosomal translocation; Complex; DNA Polymerase II; DNA-Directed RNA Polymerase; Enhancers; Family; Gene Expression; Genes; Genetic Transcription; Goals; Histones; Human; Lead; MLL gene; Malignant Neoplasms; Mixed-Lineage Leukemia; Molecular; Mutate; Mutation; Myelogenous; Oncogenes; Phosphotransferases; Positive Transcriptional Elongation Factor B; Regulation; Regulator Genes; Regulatory Element; Role; Site; Therapeutic; Transcription Elongation; Transcriptional Elongation Factors; Tumor Suppressor Proteins; combat; histone modification; leukemia; leukemia treatment; leukemogenesis; member; mutant; new therapeutic target; novel; recruit; tumor; tumorigenesis

Project Summary The mixed lineage leukemia (MLL) gene was identified due to its involvement in chromosomal translocations with a variety of translocation partners resulting in human acute myeloid or acute lymphoid leukemia. Our purification of several of the translocation partners led to the identification of the Super Elongation Complex (SEC), which includes the transcription elongation factors from the ELL family as well as the RNA Polymerase II (Pol II) c-terminal domain kinase P-TEFb. One goal of this proposal is to identify genes that are misregulated as a consequence of the chimeric protein recruiting SEC to MLL target genes, which can result in loss of the transcription elongation checkpoint control and increased expression of genes, contributing to oncogenesis. Identifying such genes could provide new therapeutic targets in the treatment of these leukemias. Another goal is to elucidate the molecular mechanisms for the recruitment of endogenous MLL as part of MLL/COMPASS and the MLL chimera/SEC to their sites on chromatin. We are also investigating the regulation of the stability of endogenous MLL and how this regulation contributes to leukemogenesis. Although MLL is frequently mutated in leukemia, the MLL3 and MLL4 branches of the COMPASS family are frequently mutated in a large number of tumors. Since MLL3 and MLL4 COMPASS regulate histone H3K4 monomethylation at transcriptional enhancers, we hypothesize that the loss of MLL3/4 COMPASS function at enhancers contributes to misexpression of tumor suppressors or oncogenes. Determining how these COMPASS mutations contribute to oncogenesis could lead to new strategies for combating these cancers.

项目概要 混合谱系白血病 (MLL) 基因因其参与染色体 与多种易位伙伴的易位导致人类急性髓系或急性淋巴系 白血病。我们对几个易位伙伴的纯化导致了超级 延伸复合体 (SEC)，其中还包括 ELL 家族的转录延伸因子 作为 RNA 聚合酶 II (Pol II) c 端结构域激酶 P-TEFb。该提案的目标之一是确定 由于嵌合蛋白将 SEC 募集到 MLL 靶基因而受到错误调节的基因， 这可能导致转录延伸检查点控制丧失并增加表达 基因，有助于肿瘤发生。识别这些基因可以提供新的治疗靶点 治疗这些白血病。另一个目标是阐明招募 内源性 MLL 作为 MLL/COMPASS 和 MLL 嵌合体/SEC 的一部分到它们在染色质上的位点。我们是 还研究了内源性 MLL 稳定性的调节以及该调节如何有助于 白血病发生。尽管 MLL 在白血病中经常发生突变，但 MLL3 和 MLL4 分支 COMPASS家族在大量肿瘤中经常发生突变。由于 MLL3 和 MLL4 COMPASS 调节转录增强子处的组蛋白 H3K4 单甲基化，我们假设 MLL3/4 COMPASS 增强子功能导致肿瘤抑制基因或癌基因的错误表达。 确定这些 COMPASS 突变如何促进肿瘤发生可能会带来新的策略 对抗这些癌症。