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: 9221587
• 负责人: EDWIN R SMITH
• 金额: $ 18.37万
• 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/9221587
• 关键词: Acute; Acute Lymphocytic Leukemia; Childhood Leukemia; Chimera organism; Chimeric Proteins; Chromatin; Chromosomal Rearrangement; Chromosomal translocation; Complex; Elongation Factor; Enhancers; Family; Gene Expression; Gene Targeting; Genes; Goals; Histones; Human; Lead; MLL gene; Malignant Neoplasms; Mixed-Lineage Leukemia; Molecular; Mutate; Mutation; Myelogenous; Oncogenes; Phosphotransferases; Positive Transcriptional Elongation Factor B; RNA Polymerase II; Recruitment Activity; Regulation; Regulatory Element; Role; Site; Therapeutic; Transcription Elongation; Tumor Suppressor Proteins; combat; histone modification; leukemia; leukemia treatment; leukemogenesis; member; mutant; new therapeutic target; novel; 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.

项目摘要 混合系白血病(MLL)基因因涉及染色体而被鉴定 与各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)，也包括ELL家族的转录延伸因子 作为RNA聚合酶II(Pol II)c-末端结构域激酶P-TEFb。这项提案的一个目标是确定 由于嵌合蛋白将SEC招募到MLL靶基因而导致调控错误的基因， 这可能导致转录延伸检查点控制的丧失和表达增加 基因，对肿瘤的发生起作用。识别这样的基因可以提供新的治疗靶点 这些白血病的治疗。另一个目标是阐明招募的分子机制 内源MLL作为MLL/COMPASS的一部分和MLL嵌合体/SEC到它们在染色质上的位置。我们是 还研究了内源性MLL稳定性的调节以及这种调节如何有助于 白血病的发生。虽然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。从ML3和MLL4指南针开始 在转录增强子上调节组蛋白H3K4单甲基化，我们假设 MLL3/4 COMPASS在增强子上的功能导致肿瘤抑制基因或癌基因的错误表达。 确定这些指南针突变如何促进肿瘤发生可能导致新的策略 与这些癌症作斗争。