Integration of the expanded genomic landscape of T-PLL with epigenetic profiles, TCR signaling competence, and drug sensitivity.

将 T-PLL 的扩展基因组景观与表观遗传图谱、TCR 信号传导能力和药物敏感性相整合。

• 批准号: 433072295
• 负责人: Dr. Marco Herling, since 12/2020
• 金额: --
• 依托单位: Institut für Humangenetik
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2020
• 资助国家: 德国
• 起止时间: 2019-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/433072295?language=en
• 关键词: Integration; expanded; genomic; landscape; PLL

T-cell prolymphocytic leukemia (T-PLL) is the most common leukemic mature T-cell lymphoma in adults. It is an overall rare (0.6 / million), poor prognostic, yet understudied tumor. T-PLL´s molecular hallmark and suspected initiating event is the constitutive transcriptional activation of the T-cell leukemia 1 (TCL1) oncogene based on a genomic inversion / translocation of chromosome 14 or its homologue Mature T cell Proliferation 1 (MTCP1) based on a translocation t(X;14). Despite TCL1´s central role in T-PLL´s pathophysiology, the mechanisms underlying the respective genomic alterations as well as TCL1s effector functions are so far not resolved. T-PLL´s chemotherapy resistance translates into an average patient survival of <20 months. There are no approved drugs for T-PLL and numerous exploratory trials to test novel options are not feasible. Aiming at the development of novel treatment strategies, first inhibitor screens uncovered promising, but also differential sensitivities. We are still far from informed implementation of new molecular knowledge into clinical application. This is mostly due to a lack of integration of available multi-level profiling data and a rudimentary understanding of their functional impact. Moreover, gene-regulatory, particularly epigenetic changes and metabolic cellular states, both also known to influence treatment responses, have not been addressed in T-PLL.Thus, we aim at establishing a comprehensive molecular map of T-PLL by integrating genomic, epigenetic, and phenotypic data (Aim 1). Using these defined molecular maps, we will (Aim 2) answer basic questions regarding the molecular mechanisms of T-PLL biology (Ulm). For that, we will describe breakpoint regions of TCL1 and MTCP1 genomic loci in order to elucidate mechanism of early T-PLL development. In addition, we will investigate the breakpoints of common secondary alterations in T-PLL. Overall, we will establish a model of deregulated networks and their underlying mechanisms by integrating genomic architecture with epigenetic and transcriptional patterns. This will enable a better basal understanding of T-PLL’s pathogenesis. Furthermore, we will (Aim 3) follow a translational approach to identify predictors of treatment responses towards available targeted compounds (Cologne). In conjunction with clinical information, we will use defined molecular alterations (including those identified in Aim 1 and Aim 2) to predict differential compound sensitivities, and to support individual treatment decisions and future trial designs. With this proposal, we apply for funding to finance additional sequencing studies. Respective complementary and subsequent work of (major parts of Aim 2 and Aim 3) is funded by the DFG and the EU / BMBF. Eventually, by developing a concept of how drug activity patterns relate to T-PLL’s molecular landscape, we will eventually identify biomarkers that discern T-PLL patient subsets based on vulnerabilities towards targeted compounds.

t细胞前淋巴细胞白血病（T-PLL）是成人中最常见的白血病成熟t细胞淋巴瘤。这是一种罕见的肿瘤（60 / 100万），预后差，尚未得到充分研究。T- pll的分子标志和可疑的起始事件是T细胞白血病1 （TCL1）癌基因基于14号染色体的基因组倒置/易位或其同系物成熟T细胞增殖1 （MTCP1）基于易位的组成性转录激活（X;14）。尽管TCL1在T-PLL的病理生理中起着核心作用，但各自基因组改变的机制以及TCL1的效应功能迄今尚未得到解决。T-PLL的化疗耐药转化为患者平均生存期<20个月。目前还没有批准的治疗T-PLL的药物，许多探索性试验也不可行。针对新的治疗策略的发展，首次抑制剂筛选发现了有希望的，但也有差异的敏感性。我们还远远没有将新的分子知识应用于临床。这主要是由于缺乏对可用的多级分析数据的集成以及对其功能影响的基本理解。此外，基因调控，特别是表观遗传变化和代谢细胞状态，都已知会影响治疗反应，但在T-PLL中尚未得到解决。因此，我们的目标是通过整合基因组、表观遗传学和表型数据，建立一个全面的T-PLL分子图谱（目的1）。使用这些定义的分子图谱，我们将（目标2）回答关于T-PLL生物学分子机制的基本问题（Ulm）。为此，我们将描述TCL1和MTCP1基因组位点的断点区域，以阐明早期T-PLL发展的机制。此外，我们将研究T-PLL常见继发性改变的断点。总体而言，我们将通过整合基因组结构与表观遗传和转录模式，建立一个解除管制网络及其潜在机制的模型。这将有助于更好地了解T-PLL的发病机制。此外，我们将（目标3）遵循翻译方法来确定对可用靶向化合物的治疗反应的预测因子（科隆）。结合临床信息，我们将使用定义的分子改变（包括Aim 1和Aim 2中确定的分子改变）来预测不同的化合物敏感性，并支持个体治疗决策和未来的试验设计。有了这个提案，我们申请资助额外的测序研究。各自的补充和后续工作（目标2和目标3的主要部分）由DFG和欧盟/ BMBF资助。最终，通过开发药物活性模式如何与T-PLL分子景观相关的概念，我们将最终确定基于对靶向化合物的脆弱性来识别T-PLL患者亚群的生物标志物。