Epigenomic Changes in Normal T-cell Development and Leukemogenesis

正常 T 细胞发育和白血病发生中的表观基因组变化

• 批准号: 7780952
• 负责人: RICHARD YOUNG
• 金额: $ 41.39万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-15 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7780952
• 关键词: Aberrant DNA Methylation; Accounting; Acute Lymphocytic Leukemia; Acute T Cell Leukemia; Binding; Biological Markers; Cell Cycle Regulation; Cell Line; Cell Lineage; Cells; Childhood Precursor T Lymphoblastic Leukemia; Chromatin; Chromosome abnormality; Clinical; Code; Complement; DNA; DNA Methylation; DNA-Directed RNA Polymerase; Development; Disease; Early Diagnosis; Epigenetic Process; Functional RNA; Gene Mutation; Gene Proteins; Genes; Genetic; Genetic Transcription; Genome; Genomics; Goals; Histones; Human; Human Cell Line; Lead; Lesion; Leukemic Cell; Link; Malignant Neoplasms; Methylation; MicroRNAs; Modeling; Modification; Molecular; Monitor; Mus; Mutation; NOTCH1 gene; Oncogenic; Pathogenesis; Patients; Play; Precipitation; Proteins; Recording of previous events; Role; Site; Sorting - Cell Movement; Staging; T cell differentiation; T-Cell Development; T-Cell Leukemia; T-Lymphocyte; TAL1 gene; Technology; Thymus Gland; base; cell type; chromatin modification; epigenomics; genome-wide; histone modification; improved; information gathering; insight; leukemia; leukemogenesis; lymphoblast; mouse model; neoplastic; notch protein; progenitor; research study; transcription factor; tumor

While significant study has been directed at understanding the genetic basis of cancer, there is growing vidence that epigenetic mechanisms also play a significant role. Epigenetic mechanisms, such as hromatin modifications and DNA methylation, are stable, long-term (typically heritable) changes in the ranscriptional potential of a cell that are independent of changes in the underlying genomic sequence. These epigenetic modifications can reveal the transcriptional history and key control mechanisms for protein-coding and miRNA genes. T-cell acute lymphoblastic leukemia (T-ALL) is a neoplastic disorder of lymphoblasts arising in the T-cell lineage. The major subtype of human T-ALL can be defined by cytogenetic abnormalities and differentiation arrest at different stages of T-cell development. NOTCH1 serves as a unifying target in this model, as activating NOTCHI mutations have now been found in all of the most common subtypes of T-ALL and in more than 50% of all pediatric T-ALL cases. Our central hypothesis is that comparing the genome-wide epigenetic signatures of T-ALL cells to normal T cell precursors will lead to substantial new insights, including the identification of genes that are differentially regulated, as well as putative markers that might lead to early diagnosis and/or improved monitoring of the progress of tumor therapies. We propose to determine the dynamic changes to cell potential using high-quality epigenetic signatures of chromatin modifications and transcriptional potential during mammalian T cell development and leukemogenesis using a NOTCH-induced mouse model (AIM 1) to determine the epigenetic mechanisms involved in progression of the T-cell leukemias. Information gathered using the mouse models will complement epigenetic state of specific subtypes of human T-ALL with defined genetic mutations (TAL1 pos, +/- NOTCH mutations) (AIM 2). The long-range goal of this proposal is to identify the transcriptional history and key epigenetic control mechanisms genome-wide for all protein-coding and miRNA genes during mammalian T cell development and T cell leukemogenesis and thus provide a critical signature of leukemic identity.

虽然已有大量研究旨在了解癌症的遗传基础，但越来越多的证据表明，表观遗传机制也起着重要作用。表观遗传机制，如染色质修饰和DNA甲基化，是细胞转录潜力的稳定、长期(通常是可遗传的)变化，与潜在基因组序列的变化无关。这些表观遗传修饰可以揭示蛋白质编码和miRNA基因的转录历史和关键控制机制。T细胞急性淋巴细胞白血病(T-ALL)是一种起源于T细胞谱系的淋巴母细胞肿瘤性疾病。人类T-ALL的主要亚型可以通过T细胞发育不同阶段的细胞遗传学异常和分化停滞来定义。NOTCH1在这个模型中是一个统一的靶点，因为激活NOTCHI突变现在已经在所有最常见的T-ALL亚型中被发现，并且在超过50%的儿童T-ALL病例中被发现。我们的中心假设是，将T-ALL细胞的全基因组表观遗传学特征与正常T细胞前体进行比较将带来实质性的新见解，包括识别差异调控的基因，以及可能导致早期诊断和/或改善对肿瘤治疗进展的监测的假定标记。我们建议在哺乳动物T细胞发育和白血病发生过程中，使用高质量的染色质修饰和转录潜能的表观遗传学特征来确定细胞潜能的动态变化，以确定表观遗传学。 T细胞白血病进展的机制。利用小鼠模型收集的信息将补充人类T-ALL特定亚型的表观遗传学状态，并确定基因突变(TAL1 pos，+/-Noch突变)(AIM 2)。这一建议的长期目标是确定哺乳动物T细胞发育和T细胞白血病发生过程中所有蛋白质编码基因和miRNA基因在基因组范围内的转录历史和关键的表观遗传控制机制，从而提供白血病身份的关键签名。