Collaborating Proteins, Affected Histone Modifications and Targets of the ALL-1 P

协作蛋白、受影响的组蛋白修饰和 ALL-1 P 的靶标

• 批准号: 8259215
• 负责人: ELI CANAANI
• 金额: $ 19.03万
• 依托单位: OHIO STATE UNIVERSITY
• 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/8259215
• 关键词: 11q23; ASCL1 gene; Acute leukemia; Affect; Age; American Society of Hematology; Binding; Biological Process; Cells; Chimeric Proteins; Chromatin; Chromosome abnormality; Chronic Lymphocytic Leukemia; Cloning; Complex; DNA Sequence Rearrangement; Data; Deposition; Disease; Enzymes; Epigenetic Process; Etiology; Foundations; Gene Targeting; Genes; Genomics; Hematopoietic; Histone H3; Histones; Homologous Gene; Human; Human Cloning; Infant; Investigation; Leukemic Cell; Location; Lysine; MLL gene; MLLT2 gene; MLLT3 gene; Methodology; Methylation; Methyltransferase; Multiprotein Complexes; Pathogenesis; Patients; Pharmaceutical Preparations; Phosphotransferases; Polycomb; Positive Transcriptional Elongation Factor B; Proteins; Recruitment Activity; Role; Technology; Testing; Transcription Elongation; Treatment Failure; Up-Regulation; Work; base; fusion gene; gene cloning; histone modification; insight; leukemia; outcome forecast; small hairpin RNA

The ALL1/MLL gene human homologue of Drosphila TRXwas previously cloned by us by virtue of its rearrangement in infant and therapy-related acute leukemia, resulting in fusion of the gene to a variety of partner genes, or in partial tandem duplication (self fusion). The ensuing fusion genes encode chimeric ALL1 proteins which directly trigger the disease. The normal ALL1 protein was shown by us to be a histone H3-lysine 4 methyltransferase which binds to its target genes to activate their expression. This proposal is based on our recent studies suggesting co-recruitment of the normal partner proteins with ALL1 fusions, identification of primary targets of ALL1 fusions, demonstrating that the UTX H3K27me3 demethylase acts in upregulation of /-/ox genes, and showing that ASH 1, like ALL1, is an H3K4 methytransferase and shares with ALL1 all targets examined. The main directions proposed will be to inquire whether the normal AF4/ENL/AF9 transeriptional elongation complex is co-recruited with all and/or some ALL1 fusions, to apply the new methodology of ChlPSeq for identification and comparison of ALL1 fusions and ALL1 targets, to check selected ALL1 fusions' targets for direct role in leukemogenicity, to examine whether H3K27me3 demethylases have a role in modulating (Hox) expression in hematopoietic cells, including those producing ALL1 fusions, further investigate function of ASH1 compared to ALL1, and ascertain whether ALL1 and not H3K4me3 is the carrier of epigenetic inheritance.

以前是由我们克隆的ranphyla trxwas的全1/mll基因人类同源物 婴儿和治疗相关的急性白血病的重排，导致基因融合到多种 伴侣基因，或部分串联复制（自融合）。随后的融合基因编码嵌合 直接触发该疾病的All1蛋白质。正常的all1蛋白显示为 组蛋白H3-赖氨酸4甲基转移酶与其靶基因结合以激活其表达。 该提案基于我们最近的研究表明，正常伙伴共同招募 具有所有1融合的蛋白质，对所有1融合的主要靶标识别，表明 UTX H3K27ME3脱甲基酶作用于 / - /ox基因的上调，并且表明Ash像All1一样是Ash 1是 H3K4甲基转移酶，并与ALL1所有目标共享。提出的主要方向 将询问正常的AF4/ENL/AF9跨性伸长率是否合并 使用所有和/或一些All1融合，将CHLPSEQ的新方法应用于识别和 比较ALL1融合和ALL1个目标，以检查选定的All1融合目标的直接作用 白血病性，检查H3K27me3脱甲基酶是否在调节（HOX）中起作用（HOX） 造血细胞中的表达，包括产生所有1融合的细胞，进一步研究功能 与All1相比，ASH1的of Ash1，并确定ALL1和不是H3K4me3是表观遗传的载体 遗产。