Epigenomic Changes in Normal T-cell Development and Leukemogenesis

虽然有意义的研究一直致力于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，是细胞转录潜能的稳定、长期（通常是可遗传的）变化，不依赖于基础基因组序列的变化。这些表观遗传修饰可以揭示蛋白质编码基因和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T细胞谱系中产生的淋巴母细胞的肿瘤性疾病。人类T-ALL的主要亚型可以通过T细胞发育的不同阶段的细胞遗传学异常和分化停滞来定义。NOTCH 1在该模型中作为统一的靶点，因为现在已经在所有最常见的T-ALL亚型和超过50%的所有儿科T-ALL病例中发现了激活NOTCH 1突变。我们的中心假设是，将T-ALL细胞的全基因组表观遗传特征与正常T细胞前体进行比较将产生大量新的见解，包括鉴定差异调节的基因，以及可能导致早期诊断和/或改善肿瘤治疗进展监测的推定标志物。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标记来确定细胞潜能的动态变化，使用NOTCH诱导的小鼠模型（AIM 1）来确定表观遗传修饰。 与T细胞白血病进展有关的机制。使用小鼠模型收集的信息将补充具有定义的遗传突变（TAL 1阳性，+/- NOTCH突变）的人T-ALL特定亚型的表观遗传状态（AIM 2）。该提案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和miRNA基因的转录历史和关键表观遗传控制机制，从而提供白血病身份的关键特征。

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.